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Vu HN, Radjasandirane R, Diharce J, de Brevern AG. Impact of Ruxolitinib Interactions on JAK2 JH1 Domain Dynamics. Int J Mol Sci 2025; 26:3727. [PMID: 40332385 PMCID: PMC12028094 DOI: 10.3390/ijms26083727] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2025] [Revised: 04/09/2025] [Accepted: 04/10/2025] [Indexed: 05/08/2025] Open
Abstract
Janus kinase 2 (JAK2) is an important intracellular mediator of cytokine signaling. Mutations in the JAK2 gene are associated with myeloproliferative neoplasms (MPNs) such as polycythemia vera (PV) and essential thrombocythemia (ET), while aberrant JAK2 activity is also associated with a number of immune diseases. The acquired somatic mutation JAK2 V617F (95% of cases of PV and in 55-60% of cases of ET), which constitutively activates the JAK2, is the most common molecular event in MPN. The development of specific JAK2 inhibitors is therefore of considerable clinical importance. Ruxolitinib is a JAK inhibitor recently approved by the FDA/EMA and effective in relieving symptoms in patients with MPN. Ruxolitinib binds to the JAK2 last domain, namely JH1; its action on the dynamics of the domain is still only partially known. Using Molecular Dynamics simulations, we have analyzed the JH1 domain in four different states as follows: (i) alone, (ii) with one phosphorylation, (iii) adding Ruxolitinib, and (iv) with five phosphorylations and Ruxolitinib. The ligand induces a dynamic behavior similar to the inactive form of JH1, with a less flexible state than the phosphorylated active form of JH1. This study highlights the inhibitory effect of Ruxolitinib on the JH1 domain, demonstrating the importance of dynamics in regulating JH1 activation.
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Affiliation(s)
- Hong Nhung Vu
- Université Paris Cité and Université de la Réunion, INSERM, EFS, BIGR U1134, DSIMB Bioinformatics Team, F-75015 Paris, France; (H.N.V.); (R.R.); (J.D.)
| | - Ragousandirane Radjasandirane
- Université Paris Cité and Université de la Réunion, INSERM, EFS, BIGR U1134, DSIMB Bioinformatics Team, F-75015 Paris, France; (H.N.V.); (R.R.); (J.D.)
| | - Julien Diharce
- Université Paris Cité and Université de la Réunion, INSERM, EFS, BIGR U1134, DSIMB Bioinformatics Team, F-75015 Paris, France; (H.N.V.); (R.R.); (J.D.)
| | - Alexandre G. de Brevern
- Université Paris Cité and Université de la Réunion, INSERM, EFS, BIGR U1134, DSIMB Bioinformatics Team, F-75015 Paris, France; (H.N.V.); (R.R.); (J.D.)
- Université Paris Cité and Université de la Réunion, INSERM, EFS, BIGR U1134, DSIMB Bioinformatics Team, F-97715 Saint Denis Messag, France
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Abreu Lopez B, Arvelaez Pascucci J, Ramzy SM, Mehta S, Daniel SS, Dave R, Rampurawala I, Pugalenthi LS, Kandambige D, Arruarana VS, Calderon Martinez E. Anagrelide in the management of essential thrombocythemia: a systemic review and meta-analysis. Int J Hematol 2025. [DOI: 10.1007/s12185-025-03959-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2025] [Revised: 02/18/2025] [Accepted: 02/20/2025] [Indexed: 04/02/2025]
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Sritana N, Cholnakasem N, Yimyaem M, Aksoramat N, Tantirukdham N, Wiriyaukaradecha K. The Janus kinase 2 (JAK2) Mutation Burden is Related to Hematological Outcomes in Thai Patients with Myeloproliferative Neoplasms. Asian Pac J Cancer Prev 2025; 26:579-586. [PMID: 40022704 PMCID: PMC12118033 DOI: 10.31557/apjcp.2025.26.2.579] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2024] [Indexed: 03/03/2025] Open
Abstract
BACKGROUND At present, data on the Janus kinase 2 (JAK2) mutation allele burden in Thai patients are limited. The aim of this study was to determine the prevalence of JAK2 V617F mutations and their association with the clinicohematological parameters of Thai patients with myeloproliferative neoplasms (MPNs). METHODS JAK2 V617F mutation status and allele burden were analyzed in 394 MPN patients using TaqMan polymerase chain reaction (PCR) probes and ARMS technology-based technique using the Ipsogen JAK2 RGQ PCR Kit. RESULTS The JAK2 V617F mutation was detected in 130 of 394 patients (32.9%). Subtype-specific JAK2 V617F detection rates were 48.1% for essential thrombocythemia (ET), 24.5% for polycythemia vera (PV), 22.2% for primary myelofibrosis (PMF) and 42.8% for Unspecified MPN patients. JAK2 V617F-positive PV and ET subtypes had a significantly higher mean age than JAK2 V617F-negative patients (p = 0.0002 and p = 0.029, respectively). The platelet (Plt) counts of JAK2 V617F-positive PV, Unspecified MPN and All groups were significantly higher than those in JAK2 V617F-negative patients (p < 0.0001, p = 0.0006 and p < 0.0001, respectively). The PMF subgroup had the highest mean JAK2 V617F allele burden (52.43 ± 34.74) compared with Unspecified MPN (51.81 ± 25.63), PV (47.38 ± 28.78) and ET patients (21.12 ± 16.34) (p < 0.0001). According to JAK2 V617F allele burden subtypes, only PV patients showed a significant increase in the white blood cell (WBC) count and hematocrit (Hct) related to incremental increases in the V617F allele burden (p < 0.0001). CONCLUSIONS The allele burden of JAK2 V617F was significantly lower in ET than in PV and PMF. Only the WBC, Hct and Plt counts were significantly different among the JAK2 V617F allele burden subgroups. Measuring the JAK2 V617F allele burden quantitatively might be an additional tool for predicting the hematological outcomes of MPNs.
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Affiliation(s)
- Narongrit Sritana
- Molecular and Genomics Research Laboratory, Chulabhorn Learning and Research Centre, Chulabhorn Royal Academy, Bangkok, Thailand.
| | - Nattida Cholnakasem
- Molecular and Genomics Research Laboratory, Chulabhorn Learning and Research Centre, Chulabhorn Royal Academy, Bangkok, Thailand.
| | - Maneenop Yimyaem
- Tissue Repository, Chulabhorn Learning and Research Centre, Chulabhorn Royal Academy, Bangkok, Thailand.
| | - Natcha Aksoramat
- Tissue Repository, Chulabhorn Learning and Research Centre, Chulabhorn Royal Academy, Bangkok, Thailand.
| | - Nithiphut Tantirukdham
- Molecular and Genomics Research Laboratory, Chulabhorn Learning and Research Centre, Chulabhorn Royal Academy, Bangkok, Thailand.
| | - Kriangpol Wiriyaukaradecha
- Molecular and Genomics Research Laboratory, Chulabhorn Learning and Research Centre, Chulabhorn Royal Academy, Bangkok, Thailand.
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Drofenik A, Blinc A, Bozic Mijovski M, Pajic T, Vrtovec M, Sever M. Relation of JAK2 V617F allele burden and coronary calcium score in patients with essential thrombocythemia. Radiol Oncol 2024; 58:565-572. [PMID: 39361963 PMCID: PMC11604290 DOI: 10.2478/raon-2024-0036] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2024] [Accepted: 06/01/2024] [Indexed: 10/05/2024] Open
Abstract
BACKGROUND JAK2 V617F (JAK2) mutation is associated with clonal hemopoiesis in myeloproliferative neoplasms as well as with faster progression of cardiovascular diseases. Little is known about the relationship between allele burden and the degree of atherosclerotic alteration of coronary vasculature. We previously reported that carotid artery stiffness progressed faster in patients with JAK2 positive essential thromocythemia (ET) patients. After a four-year follow-up we investigated whether mutation burden of a JAK2 allele correlates with a higher coronary calcium score. PATIENTS AND METHODS Thirty-six patients with JAK2 positive ET and 38 healthy matched control subjects were examined twice within four years. At each visit clinical baseline characteristics and laboratory testing were performed, JAK2 mutation burden was determined, and coronary calcium was measured. RESULTS JAK2 allele burden decreased in 19 patients, did not change in 5 patients, and increased in 4 patients. The coronary calcium Agatston score increased slightly in both groups. Overall, there was no correlation between JAK2 allele burden and calcium burden of coronary arteries. However, in patients with the JAK2 mutation burden increase, the coronary calcium score increased as well. CONCLUSIONS The average JAK2 allele burden decreased in our patients with high-risk ET during the four-year period. However, in the small subgroup whose JAK2 mutation burden increased the Agatston coronary calcium score increased as well. This finding, which should be interpreted with caution and validated in a larger group, is in line with emerging evidence that JAK2 mutation accelerates atherosclerosis and can be regarded as a non-classical risk factor for cardiovascular disease.
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Affiliation(s)
- Ajda Drofenik
- Department of Cardiology, Division of Internal Medicine, University Medical Centre Ljubljana, Ljubljana, Slovenia
| | - Ales Blinc
- Department of Vascular Diseases, Division of Internal Medicine, University Medical Centre Ljubljana, Ljubljana, Slovenia
- Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Mojca Bozic Mijovski
- Department of Vascular Diseases, Division of Internal Medicine, University Medical Centre Ljubljana, Ljubljana, Slovenia
- Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia
| | - Tadej Pajic
- Clinical Institute for Genomic Medicine, University Medical Centre Ljubljana, Ljubljana, Slovenia
- Faculty of Medicine, University of Maribor, Maribor, Slovenia
| | - Matjaz Vrtovec
- Department of Vascular Diseases, Division of Internal Medicine, University Medical Centre Ljubljana, Ljubljana, Slovenia
- Department of Dermatovenerology, University Medical Centre Ljubljana, Ljubljana, Slovenia
| | - Matjaz Sever
- Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
- Department of Haematology, Division of Internal Medicine, University Medical Centre Ljubljana, Ljubljana, Slovenia
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Sayed WS, Al-Bayati A, Elzubair LG, Mohamed S, Alharthi M. The Association Between Janus Kinase 2 and Factor V Leiden Mutations and Thrombotic Complications in Patients With Myeloproliferative Disorders: A Study From Saudi Arabia. Cureus 2024; 16:e74401. [PMID: 39723287 PMCID: PMC11669263 DOI: 10.7759/cureus.74401] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/24/2024] [Indexed: 12/28/2024] Open
Abstract
Background The Janus kinase 2 (JAK2) V617F mutations are related to increased thrombotic risk in patients with myeloproliferative disorders (MPDs). However, little is known about whether inherited thrombophilia represents an additive risk factor in mutated subjects. We addressed the association between combined mutations of JAK2 and factor V Leiden (FVL) and thrombotic complications in Saudi Arabian patients with MPDs. Methods We studied 60 patients with MPDs, 32 with polycythemia vera (PV), 24 with essential thrombocythemia (ET), and four with primary myelofibrosis (PMF). All patients were examined for JAK2 V617F and FVL mutations. Results The study included 50 (83.3%) males and 10 (16.7%) females, with a mean age of 44.23 ± 11.32 years. JAK2 was found positive among all (100%) of the studied patients. Thirty-eight patients out of 60 (63.3%) had thrombotic events. FVL was found positive in 12 (20%) patients. The patients with JAK2 and FVL mutations had a higher incidence of thrombotic events (11/38, 28.9%) than those with JAK2 but without FVL mutations (1/22, 4.5%). The relative risk ratios for increased risk for having thrombotic events were 2.1 (95% confidence interval (95% CI): 1.2-3.8, p=0.03) and 4.3 (95% CI: 2.1-9.5, p<0.001) for patients with JAK2 mutations alone, and those with both JAK2 and FVL mutations, respectively. Conclusions In the present study of patients with MPDs from Saudi Arabia, JAK2 mutations were found among all the studied patients, and FVL mutations were encountered in 20% of patients. The patients with both JAK2 and FVL mutations had a higher incidence of thrombotic events than those with JAK2 but without FVL mutations. The relative risk ratios for increased risk for thrombotic events among patients with MPDs were 2.1 and 4.3 for patients with JAK2 mutations alone and those with JAK2 and FVL mutations, respectively. Further larger prospective studies are warranted.
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Affiliation(s)
- Wafaa S Sayed
- Clinical Pathology, Aswan University Hospital, Aswan, EGY
- Clinical Pathology, Khamis Mushait General Hospital, Khamis Mushait, SAU
| | - Aws Al-Bayati
- Clinical Hematology, Armed Forces Hospital - Southern Region, Khamis Mushait, SAU
| | - Lina G Elzubair
- Haematopathology, Armed Forces Hospital - Southern Region, Khamis Mushait, SAU
| | - Sherif Mohamed
- Chest Diseases and Tuberculosis, Faculty of Medicine, Assiut University, Assiut, EGY
- Internal Medicine, Prince Sultan Bin Abdulaziz Humanitarian City, Riyadh, SAU
| | - Mueed Alharthi
- Clinical Hematology, Khamis Mushait General Hospital, Khamis Mushait, SAU
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Patel R, DeRon N. Newly diagnosed essential thrombocythemia leading to cardiogenic shock: a case report. BMC Cardiovasc Disord 2024; 24:579. [PMID: 39434013 PMCID: PMC11492626 DOI: 10.1186/s12872-024-04263-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2024] [Accepted: 10/14/2024] [Indexed: 10/23/2024] Open
Abstract
BACKGROUND Essential thrombocythemia (ET) is a myeloproliferative neoplasm characterized by uninhibited platelet production. It can present with vasomotor symptoms, and less commonly, severe thrombotic events such as myocardial infarction. ST-segment elevation myocardial infarction (STEMI) secondary to the hypercoagulable state in ET is a diagnostic challenge as the complication is rare, especially outside the typical demographics affected by ET such as the female and elderly populations. CASE PRESENTATION Here we report a case of a 32-year-old male found to have STEMI and a markedly elevated platelet count. Angiography revealed occlusion of the left anterior descending and left circumflex arteries, requiring percutaneous intervention and Impella support. The patient was later diagnosed with essential thrombocythemia, treated with hydroxyurea and antiplatelet therapy, and discharged with a wearable cardioverter defibrillator. CONCLUSIONS This case illustrates the potential for severe thrombotic complications such as STEMI due to ET. Severe thrombotic complications are less common manifestations of ET in general, particularly in young males. Recognition and diagnosis of ET are critical for the institution of appropriate therapy and prevention of STEMI and cardiogenic shock among other complications.
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Affiliation(s)
- Ravi Patel
- Department of Internal Medicine, Methodist Dallas Medical Center, 1441 N Beckley Ave, Dallas, TX, 75203, USA.
| | - Nathan DeRon
- Department of Internal Medicine, Methodist Dallas Medical Center, 1441 N Beckley Ave, Dallas, TX, 75203, USA
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Al-Mashdali AF, Aldapt MB, Rahhal A, Hailan YM, Elhakeem I, Ali EA, Rozi W, Yassin MA. Pediatric Philadelphia-Negative Myeloproliferative Neoplasms in the Era of WHO Classification: A Systematic Review. Diagnostics (Basel) 2023; 13:diagnostics13030377. [PMID: 36766480 PMCID: PMC9914355 DOI: 10.3390/diagnostics13030377] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2022] [Revised: 01/13/2023] [Accepted: 01/17/2023] [Indexed: 01/21/2023] Open
Abstract
BACKGROUND Philadelphia-negative myeloproliferative neoplasms (MPN) are most prevalent in the older population (median age at the diagnosis is above 60 years) and rarely diagnosed in pediatrics. Thus, our knowledge about the clinical presentation, mutational status, and complications of MPNs in pediatrics is limited. METHODS The literature in English (PubMed, SCOPUS, and Google Scholar) was searched for studies, reviews, case series, and case reports of patients with Philadelphia-negative MPNs (including essential thrombocythemia, polycythemia vera, primary myelofibrosis, and profibrotic myelofibrosis) in the pediatrics age group (less than 18 years). Only studies that fulfilled WHO 2008 or 2016 criteria for MPNs were included. We aimed to describe the clinical characteristics, vascular and long-term complications, types of driver mutations, and treatment approaches in pediatric patients with MPNs. RESULTS We reviewed 33 articles of available published literature from 2008 to 2022 and collected data from a total of 196 patients of the pediatric population. Among the cohort of patients, 139 had essential thrombocythemia (ET), 20 had polycythemia vera (PV), and 37 had primary myelofibrosis (PMF). The median age at the time of diagnosis for each disease varied, with 8.8 years for ET, 10 years for PV, and 3.6 years for MF. There was a slight difference in gender prevalence between both gender groups and all three diseases. The presenting symptoms were not mentioned in more than 50% of studies. We found that JAK2 was the most prevalent among all mutations. Both bleeding and thrombosis were present equally in ET, with 9% of cases complicated by bleeding and 9% complicated by thrombosis. Hemorrhagic events did not occur in patients with PV; thrombosis in children with MF was also not found. The progression into AML occurred in two patients with PV and one with ET. CONCLUSION Given the rarity of MPNs in pediatrics and their different characteristics compared with adults, we believe there is a need for unique diagnostic criteria to match the different molecular statuses in pediatrics. Based on our review, the incidence of MPN complications in pediatrics, including thrombotic events, hemorrhage, and leukemic transformation, differs from that in adults.
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Affiliation(s)
- Abdulrahman F. Al-Mashdali
- Department of Internal Medicine, Hamad Medical Corporation, Doha 3050, Qatar
- Correspondence: or (A.F.A.-M.); (M.A.Y.)
| | - Mahmood B. Aldapt
- Department of Medicine, Unity Hospital, Rochester Regional Health, Rochester, NY 14626, USA
| | - Alaa Rahhal
- Pharmacy Department, Hamad Medical Corporation, Doha 3050, Qatar
| | - Yousef M. Hailan
- Department of Internal Medicine, Hamad Medical Corporation, Doha 3050, Qatar
| | - Israa Elhakeem
- Clinical Oncology, Hamad Medical Corporation, Doha 3050, Qatar
| | - Elrazi A. Ali
- One Brooklyn Health, Interfaith Medical Center, Internal Medicine Department, Brooklyn, NY 11213, USA
| | - Waail Rozi
- Department of Internal Medicine, Hamad Medical Corporation, Doha 3050, Qatar
| | - Mohamed A. Yassin
- National Center for Cancer Care and Research, Department of Oncology, Hematology and BMT Section, Hamad Medical Corporation, Doha 3050, Qatar
- Correspondence: or (A.F.A.-M.); (M.A.Y.)
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Mittelman A, Nnadi C, Sadrzadeh H, Andreeva E. A woman presenting with facial droop. J Am Coll Emerg Physicians Open 2022; 3:e12827. [PMID: 36187505 PMCID: PMC9512762 DOI: 10.1002/emp2.12827] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Accepted: 08/31/2022] [Indexed: 11/08/2022] Open
Affiliation(s)
- Andrew Mittelman
- Department of Emergency MedicineBoston University School of MedicineBostonMassachusettsUnited States
- Department of Emergency MedicineBoston Medical CenterBostonMassachusetts
| | - Chisom Nnadi
- Department of Emergency MedicineBoston Medical CenterBostonMassachusetts
| | - Hossein Sadrzadeh
- Department of Hematology and OncologyBoston Medical CenterBostonMassachusetts
| | - Elmira Andreeva
- Department of Emergency MedicineBoston Medical CenterBostonMassachusetts
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KAHRAMAN S, DEMİRKAN F. Assessment of relation between JAK2 gene and thrombosis in myeloproliferative neoplasms. TURKISH JOURNAL OF INTERNAL MEDICINE 2022. [DOI: 10.46310/tjim.1055305] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022] Open
Abstract
Background Thrombotic complications are the most considerable etiology causing morbidity and mortality in patients with philadelphia (Ph) negative myeloproliferative neoplasms (MPN). There are many studies evaluating the association of JAK2 mutation and risk of thrombosis in MPN with inconclusive results. We also investigated the relation between JAK2 mutation in all Ph negative MPN and thrombosis.
Material and Methods Thrombotic events and demographic features of 177 patients with Ph negative MPN were evaluated retrospectively.
Results JAK2 V617 F mutation was detected in 57% of patients with essential thrombocythemia (ET), %90.3 of pateints with polycythemia vera (PV), 100% of pateints with primary myelofibrosis (PMF). Thrombotic complications occured more frequently with JAK2 mutation in all MPN patients than without (p=0.014). In JAK 2 mutation positive groups, the median age, thrombosis risk scores and leucocyte values are higher, splenomegaly and arterial and/or venous thrombosis are detected more frequently (p
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Gou P, Zhang W, Giraudier S. Insights into the Potential Mechanisms of JAK2V617F Somatic Mutation Contributing Distinct Phenotypes in Myeloproliferative Neoplasms. Int J Mol Sci 2022; 23:ijms23031013. [PMID: 35162937 PMCID: PMC8835324 DOI: 10.3390/ijms23031013] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Revised: 01/09/2022] [Accepted: 01/13/2022] [Indexed: 12/19/2022] Open
Abstract
Myeloproliferative neoplasms (MPN) are a group of blood cancers in which the bone marrow (BM) produces an overabundance of erythrocyte, white blood cells, or platelets. Philadelphia chromosome-negative MPN has three subtypes, including polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). The over proliferation of blood cells is often associated with somatic mutations, such as JAK2, CALR, and MPL. JAK2V617F is present in 95% of PV and 50–60% of ET and PMF. Based on current molecular dynamics simulations of full JAK2 and the crystal structure of individual domains, it suggests that JAK2 maintains basal activity through self-inhibition, whereas other domains and linkers directly/indirectly enhance this self-inhibited state. Nevertheless, the JAK2V617F mutation is not the only determinant of MPN phenotype, as many normal individuals carry the JAK2V617F mutation without a disease phenotype. Here we review the major MPN phenotypes, JAK-STAT pathways, and mechanisms of development based on structural biology, while also describing the impact of other contributing factors such as gene mutation allele burden, JAK-STAT-related signaling pathways, epigenetic modifications, immune responses, and lifestyle on different MPN phenotypes. The cross-linking of these elements constitutes a complex network of interactions and generates differences in individual and cellular contexts that determine the phenotypic development of MPN.
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Affiliation(s)
- Panhong Gou
- Laboratoire UMRS-1131, Ecole doctorale 561, Université de Paris, 75010 Paris, France
- INSERM UMR-S1131, Hôpital Saint-Louis, 75010 Paris, France
- Correspondence: (P.G.); (S.G.)
| | - Wenchao Zhang
- BFA, UMR 8251, CNRS, Université de Paris, 75013 Paris, France;
| | - Stephane Giraudier
- Laboratoire UMRS-1131, Ecole doctorale 561, Université de Paris, 75010 Paris, France
- INSERM UMR-S1131, Hôpital Saint-Louis, 75010 Paris, France
- Service de Biologie Cellulaire, Hôpital Saint-Louis, AP-HP, 75010 Paris, France
- Correspondence: (P.G.); (S.G.)
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The Prognostic Role of Cytogenetics Analysis in Philadelphia Negative Myeloproliferative Neoplasms. ACTA ACUST UNITED AC 2021; 57:medicina57080813. [PMID: 34441019 PMCID: PMC8398709 DOI: 10.3390/medicina57080813] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2021] [Revised: 08/03/2021] [Accepted: 08/06/2021] [Indexed: 11/16/2022]
Abstract
Myeloproliferative neoplasms (MPNs) are clonal stem cell disorders characterized collectively by clonal proliferation of myeloid cells with variable morphologic maturity and hematopoietic efficiency. Although the natural history of these neoplasms can be measured sometimes in decades more than years, the cytogenetics analysis can offer useful information regarding the prognosis. Cytogenetics has a well-established prognostic role in acute leukemias and in myelodysplastic syndromes, where it drives the clinical decisions. NGS techniques can find adverse mutations with clear prognostic value and are currently included in the prognostic evaluation of MPNs in scores such as MIPSS, GIPSS, MIPSS-PV, and MIPSS-ET. We suggest that cytogenetics (considering its availability and relative cost) has a role regarding prognostic and therapeutic decisions.
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Das S, Deb A, Pal T. Antithrombotic Management in Ischemic Stroke with Essential Thrombocythemia: Current Evidence and Dilemmas. Med Princ Pract 2021; 30:412-421. [PMID: 33849034 PMCID: PMC8562054 DOI: 10.1159/000516471] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2020] [Accepted: 04/10/2021] [Indexed: 12/11/2022] Open
Abstract
Thrombotic diseases like ischemic stroke are common complications of essential thrombocythemia (ET) due to abnormal megakaryopoiesis and platelet dysfunction. Ischemic stroke in ET can occur as a result of both cerebral arterial and venous thrombosis. Management of ET is aimed at preventing vascular complications including thrombosis. Acute management of ischemic stroke in ET is the same as that in the general population without myeloproliferative disorders. However, an ET patient with ischemic stroke is at high risk for rethrombosis and is therefore additionally managed with cytoreductive therapy and antithrombotic agents. Given abnormal platelet production in ET, there is suboptimal suppression of platelets with the standard recommended dose of aspirin for cardiovascular (CV) prevention. Hence, for optimal CV protection in ET, low-dose aspirin is recommended twice daily in an arterial thrombotic disease like atherothrombotic ischemic stroke in presence of the following risk factors: age >60 years, Janus kinase2 V617F gene mutation, and presence of CV risk factors. In the presence of the same risk factors, concurrent antiplatelet and anticoagulant therapy is suggested for venous thrombosis. However, increased risk of bleeding with dual antithrombotic agents poses a significant challenge in their use in cerebral venous thromboembolism or atrial fibrillation in presence of the above-mentioned risk factors. We discuss these dilemmas regarding antithrombotic management in ischemic stroke in ET in this case-based review of literature in the light of current evidence.
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Affiliation(s)
- Shubhabrata Das
- Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Anasua Deb
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, Texas, USA
| | - Tanmoy Pal
- Department of Neurology, Neotia Getwel Healthcare Centre, Siliguri, India
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Makarik TV, Abdullaev AO, Nikulina EE, Treglazova SA, Stepanova EE, Subortseva IN, Kovrigina AM, Melikyan AL, Kulikov SM, Sudarikov AB. Low JAK2 V617F Allele Burden in Ph-Negative Chronic Myeloproliferative Neoplasms Is Associated with Additional CALR or MPL Gene Mutations. Genes (Basel) 2021; 12:genes12040559. [PMID: 33921387 PMCID: PMC8069892 DOI: 10.3390/genes12040559] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2021] [Revised: 04/07/2021] [Accepted: 04/08/2021] [Indexed: 01/08/2023] Open
Abstract
JAK2 (Janus kinase 2) V617F, CALR (Calreticulin) exon 9, and MPL (receptor for thrombopoietin) exon 10 mutations are associated with the vast majority of Ph-negative chronic myeloproliferative neoplasms (MPNs). These mutations affect sequential stages of proliferative signal transduction and therefore, after the emergence of one type of mutation, other types should not have any selective advantages for clonal expansion. However, simultaneous findings of these mutations have been reported by different investigators in up to 10% of MPN cases. Our study includes DNA samples from 1958 patients with clinical evidence of MPN, admitted to the National Research Center for Hematology for genetic analysis between 2016 and 2019. In 315 of 1402 cases (22.6%), CALR mutations were detected. In 23 of these 315 cases (7.3%), the JAK2 V617F mutation was found in addition to the CALR mutation. In 16 from 24 (69.6%) cases, with combined CALR and JAK2 mutations, V617F allele burden was lower than 1%. A combination of JAK2 V617F with MPL W515L/K was also observed in 1 out of 1348 cases, only. JAK2 allele burden in this case was also lower than 1%. Additional mutations may coexist over the low background of JAK2 V617F allele. Therefore, in cases of detecting MPNs with a low allelic load JAK2 V617F, it may be advisable to search for other molecular markers, primarily mutations in exon 9 of CALR. The load of the combined mutations measured at different time points may indicate that, at least in some cases, these mutations could be represented by different clones of malignant cells.
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14
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Ali EA, Nashwan AJ, Yassin MA. Essential thrombocythemia with (type2) calreticulin presented as stuttering priapism case report and review of literature. Clin Case Rep 2021; 9:399-404. [PMID: 33489189 PMCID: PMC7813073 DOI: 10.1002/ccr3.3541] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2020] [Revised: 08/16/2020] [Accepted: 09/08/2020] [Indexed: 12/14/2022] Open
Abstract
Priapism is a rare presentation and complication of ET that might be underreported. In ET, priapism can present as an ischemic or stuttering type. These patients are more likely to be anemic and have a high platelet count.
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Affiliation(s)
| | | | - Mohamed A Yassin
- Hematology and Oncology DepartmentHamad Medical CorporationDohaQatar
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15
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Garrido-Trigo A, Salas A. Molecular Structure and Function of Janus Kinases: Implications for the Development of Inhibitors. J Crohns Colitis 2020; 14:S713-S724. [PMID: 32083640 PMCID: PMC7395311 DOI: 10.1093/ecco-jcc/jjz206] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Cytokines can trigger multiple signalling pathways, including Janus tyrosine kinases [JAK] and signal transducers and activators of transcription [STATS] pathways. JAKs are cytoplasmic proteins that, following the binding of cytokines to their receptors, transduce the signal by phosphorylating STAT proteins which enter the nuclei and rapidly target gene promoters to regulate gene transcription. Due to the critical involvement of JAK proteins in mediating innate and adaptive immune responses, these family of kinases have become desirable pharmacological targets in inflammatory diseases, including ulcerative colitis and Crohn's disease. In this review we provide an overview of the main cytokines that signal through the JAK/STAT pathway and the available in vivo evidence on mutant or deleted JAK proteins, and discuss the implications of pharmacologically targeting this kinase family in the context of inflammatory diseases.
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Affiliation(s)
- Alba Garrido-Trigo
- Department of Gastroenterology, Institut d’Investigacions Biomèdiques August Pi i Sunyer [IDIBAPS] – CIBEREHD, Barcelona, Spain
| | - Azucena Salas
- Department of Gastroenterology, Institut d’Investigacions Biomèdiques August Pi i Sunyer [IDIBAPS] – CIBEREHD, Barcelona, Spain,Corresponding author: Azucena Salas, PhD, Inflammatory Bowel Disease Unit, Department of Gastroenterology, Institut d’Investigacions Biomèdiques August Pi i Sunyer [IDIBAPS] – CIBEREHD, Rosselló 149-153, Barcelona 08036, Spain.
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16
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Pedersen RK, Andersen M, Knudsen TA, Sajid Z, Gudmand-Hoeyer J, Dam MJB, Skov V, Kjaer L, Ellervik C, Larsen TS, Hansen D, Pallisgaard N, Hasselbalch HC, Ottesen JT. Data-driven analysis of JAK2V617F kinetics during interferon-alpha2 treatment of patients with polycythemia vera and related neoplasms. Cancer Med 2020; 9:2039-2051. [PMID: 31991066 PMCID: PMC7064092 DOI: 10.1002/cam4.2741] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2019] [Revised: 11/13/2019] [Accepted: 11/15/2019] [Indexed: 12/22/2022] Open
Abstract
Treatment with PEGylated interferon-alpha2 (IFN) of patients with essential thrombocythemia and polycythemia vera induces major molecular remissions with a reduction in the JAK2V617F allele burden to undetectable levels in a subset of patients. A favorable response to IFN has been argued to depend upon the tumor burden, implying that institution of treatment with IFN should be as early as possible after the diagnosis. However, evidence for this statement is not available. We present a thorough analysis of unique serial JAK2V617F measurements in 66 IFN-treated patients and in 6 untreated patients. Without IFN treatment, the JAK2V617F allele burden increased exponentially with a period of doubling of 1.4 year. During monotherapy with IFN, the JAK2V617F allele burden decreased mono- or bi-exponentially for 33 responders of which 28 patients satisfied both descriptions. Bi-exponential description improved the fits in 19 cases being associated with late JAK2V617F responses. The decay of the JAK2V617F allele burden during IFN treatment was estimated to have half-lives of 1.6 year for the monoexponential response and 1.0 year in the long term for the bi-exponential response. In conclusion, through data-driven analysis of the JAK2V617F allele burden, we provide novel information regarding the JAK2V617F kinetics during IFN-treatment, arguing for early intervention.
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Affiliation(s)
- Rasmus K Pedersen
- Department of Science and Environment, Roskilde University, Roskilde, Denmark
| | - Morten Andersen
- Department of Science and Environment, Roskilde University, Roskilde, Denmark
| | - Trine A Knudsen
- Department of Haematology, Zealand University Hospital, Roskilde, Denmark
| | - Zamra Sajid
- Department of Science and Environment, Roskilde University, Roskilde, Denmark
| | | | - Marc J B Dam
- Department of Science and Environment, Roskilde University, Roskilde, Denmark
| | - Vibe Skov
- Department of Haematology, Zealand University Hospital, Roskilde, Denmark
| | - Lasse Kjaer
- Department of Haematology, Zealand University Hospital, Roskilde, Denmark
| | - Christina Ellervik
- Department of Production, Research, and Innovation, Region Zealand, Sorø, Denmark.,Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.,Department of Pathology, Harvard Medical School, Boston, FL, USA.,Department of Laboratory Medicine, Boston Children's Hospital, Boston, FL, USA
| | - Thomas S Larsen
- Department of Hematology, Odense University Hospital, Odense, Denmark
| | - Dennis Hansen
- Department of Hematology, Odense University Hospital, Odense, Denmark
| | - Niels Pallisgaard
- Department of Surgical Pathology, Zealand University Hospital, Roskilde, Denmark
| | - Hans C Hasselbalch
- Department of Haematology, Zealand University Hospital, Roskilde, Denmark
| | - Johnny T Ottesen
- Department of Science and Environment, Roskilde University, Roskilde, Denmark
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17
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Medina Vega L, Hernández Nieto L, Salido Ruíz E, Álvarez-Argüelles Cabrera H, Raya Sánchez J. Análisis integrado clínico, molecular e histopatológico de la médula ósea en las neoplasias mieloproliferativas crónicas. Rev Clin Esp 2019; 219:440-444. [DOI: 10.1016/j.rce.2018.11.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2018] [Revised: 11/16/2018] [Accepted: 11/26/2018] [Indexed: 10/27/2022]
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18
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Medina Vega L, Hernández Nieto L, Salido Ruíz E, Álvarez-Argüelles Cabrera H, Raya Sánchez J. Comprehensive clinical, molecular and histopathological analysis of bone marrow in chronic myeloproliferative neoplasia. Rev Clin Esp 2019. [DOI: 10.1016/j.rceng.2018.11.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
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19
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Soucy-Giguère MC, Turgeon PY, Sénéchal M. What cardiologists should know about essential thrombocythemia and acute myocardial infarction: report of two cases and advanced heart failure therapies considerations. Int Med Case Rep J 2019; 12:253-259. [PMID: 31496834 PMCID: PMC6690852 DOI: 10.2147/imcrj.s217568] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2019] [Accepted: 07/09/2019] [Indexed: 11/23/2022] Open
Abstract
We present the cases of two young male patients aged 22 and 31 without prior medical history nor cardiovascular risk factors, who presented to the hospital with large anterior ST-elevation myocardial infarction (STEMI). Urgent coronary angiography revealed acute thrombotic occlusion of the proximal left anterior descending artery in both patients. Persistent thrombocytosis was noted and subsequent investigations led to the diagnosis of essential thrombocythemia (ET) with positive JAK2-V617F mutation. Myocardial infarction as a first clinical manifestation of ET is rare but must be considered in patients without cardiovascular risk factors who show persistent thrombocytosis. In young patients without risk factors, there may be great delays before the diagnosis of STEMI is made. Longer time to revascularization of extensive STEMI is associated with adverse outcomes and cardiogenic shock which can lead to advanced therapies like heart transplant and left ventricular assist device (LVAD). Considering the favorable long-term prognosis of patients with ET, advanced therapies may be a valuable option in the presence of severe left ventricular dysfunction.
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Affiliation(s)
- Marie-Camille Soucy-Giguère
- Department of Cardiology, Institut Universitaire de Cardiologie et de Pneumologie de Québec, Québec City, QC, Canada
| | - Pierre Yves Turgeon
- Department of Cardiology, Institut Universitaire de Cardiologie et de Pneumologie de Québec, Québec City, QC, Canada
| | - Mario Sénéchal
- Department of Cardiology, Institut Universitaire de Cardiologie et de Pneumologie de Québec, Québec City, QC, Canada
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20
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Hsieh RW, Ravindran A, Hook CC, Begna KH, Ashrani AA, Pruthi RK, Marshall AL, Hogan W, Litzow M, Hoyer J, Oliveira JL, Vishnu P, Call TG, Al-Kali A, Patnaik M, Gangat N, Pardanani A, Tefferi A, Go RS. Etiologies of Extreme Thrombocytosis: A Contemporary Series. Mayo Clin Proc 2019; 94:1542-1550. [PMID: 31378229 DOI: 10.1016/j.mayocp.2019.01.041] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2018] [Revised: 12/25/2018] [Accepted: 01/23/2019] [Indexed: 11/22/2022]
Abstract
OBJECTIVE To describe the multifactorial etiologies of extreme thrombocytosis (EXT) in different care settings and the frequency of finding an occult malignancy. PATIENTS AND METHODS We conducted a retrospective chart review at Mayo Clinic from January 1, 2011, through December 31, 2016. Adult patients who had at least 2 readings of platelet counts greater than 1000×109/L within 30 days of each other were included. We determined the causes of EXT on the basis of preset definitions of precipitating factors and identified the dominant causes on the basis of the trend of platelet counts. RESULTS A total of 44,490 patients had thrombocytosis, and 305 patients (0.7%) had EXT. In 242 patients (79.3%), EXT was multifactorial. Surgical complications (54.1%) and hematologic malignancies (27.9%) were the 2 most dominant causes. Thirty-eight patients (12.5%) had new diagnoses of malignancies, mostly myeloproliferative neoplasms. In inpatients, surgical complications (71.9%), concurrent/previous splenectomy (50.5%), and infections (44.9%) were the most common causes, whereas hematologic malignancies (56.9%), iron deficiency (36.7%), and previous splenectomy (28.4%) were the most common causes in outpatients. Hematologic malignancy was 3.4 times more likely to be the cause of EXT in outpatients than in inpatients (56.9% vs 16.8%), and a new diagnosis of hematologic malignancy was 1.9 times more likely to be made in outpatients (15.6% vs 8.2%). Eighty-four percent of patients had resolution of EXT within 30 days. One patient died during the period of EXT. Nonsurgical patients with hematologic malignancies had the most prolonged period of EXT. CONCLUSION Extreme thrombocytosis is a multifactorial hematologic condition, and its etiology differs substantially between inpatients and outpatients. Occult hematologic malignancies are uncommon in EXT when other major causes are present.
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Affiliation(s)
- Ronan W Hsieh
- Division of Hematology, Mayo Clinic, Rochester, MN; Department of Medicine, Albert Einstein Medical Center, Philadelphia, PA
| | - Aishwarya Ravindran
- Division of Hematology, Mayo Clinic, Rochester, MN; Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN
| | | | | | | | | | | | | | - Mark Litzow
- Division of Hematology, Mayo Clinic, Rochester, MN
| | - James Hoyer
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN
| | | | | | | | - Aref Al-Kali
- Division of Hematology, Mayo Clinic, Rochester, MN
| | | | | | | | | | - Ronald S Go
- Division of Hematology, Mayo Clinic, Rochester, MN.
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21
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Yoshida K, Kurihara I, Fukuchi T, Sugawara H. Acute splenic infarction presenting as an unusual manifestation of essential thrombocythaemia with normal platelet count. BMJ Case Rep 2019; 12:12/7/e229387. [PMID: 31272993 DOI: 10.1136/bcr-2019-229387] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022] Open
Abstract
Essential thrombocythaemia (ET) is characterised by elevated platelet count by a clonal stem cell disorder of megakaryocytes. Although thrombosis is a common complication of ET, splenic infarction (SI) is extremely rare. Here, we present the case of a 31-year-old Japanese man who presented with sudden-onset severe pain at the left hypochondrium on the day before admission. Enhanced abdominal CT revealed SI. The laboratory test results revealed a normal platelet count (439×109/L). Subsequently, the patient was diagnosed with ET because the platelet count gradually increased to 50.0×104/μL, and JAK2 V617F mutation was identified. Accordingly, low-dose aspirin was initiated, and no thrombotic episode occurred. Nevertheless, 6 months postdischarge, the platelet count gradually increased to >650 × 109/L, and anagrelide was initiated. This case demonstrates an unusual complication of acute SI due to ET under the rare situation of the normal platelet count.
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Affiliation(s)
- Katsuyuki Yoshida
- Division of General Medicine, Department of Comprehensive Medicine 1, Jichi Ika Daigaku Fuzoku Saitama Iryo Center, Saitama, Japan
| | - Ibuki Kurihara
- Division of General Medicine, Department of Comprehensive Medicine 1, Jichi Ika Daigaku Fuzoku Saitama Iryo Center, Saitama, Japan
| | - Takahiko Fukuchi
- Division of General Medicine, Department of Comprehensive Medicine 1, Jichi Ika Daigaku Fuzoku Saitama Iryo Center, Saitama, Japan
| | - Hitoshi Sugawara
- Division of General Medicine, Department of Comprehensive Medicine 1, Jichi Ika Daigaku Fuzoku Saitama Iryo Center, Saitama, Japan
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22
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Tavares RS, Nonino A, Pagnano KBB, Nascimento ACKVD, Conchon M, Fogliatto LM, Funke VAM, Bendit I, Clementino NCD, Chauffaille MDLLF, Bernardo WM, Santos FPDS. Guideline on myeloproliferative neoplasms: Associacão Brasileira de Hematologia, Hemoterapia e Terapia Cellular: Project guidelines: Associação Médica Brasileira - 2019. Hematol Transfus Cell Ther 2019; 41 Suppl 1:1-73. [PMID: 31248788 PMCID: PMC6630088 DOI: 10.1016/j.htct.2019.03.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2019] [Accepted: 03/20/2019] [Indexed: 12/22/2022] Open
Affiliation(s)
| | - Alexandre Nonino
- Instituto Hospital de Base do Distrito Federal (IHBDF), Brasília, DF, Brazil
| | | | | | | | | | | | - Israel Bendit
- Hospital Das Clínicas da Faculdade de Medicina da Universidade de São Paulo (HCFMUSP), São Paulo, SP, Brazil
| | | | | | - Wanderley Marques Bernardo
- Hospital Das Clínicas da Faculdade de Medicina da Universidade de São Paulo (HCFMUSP), São Paulo, SP, Brazil; Associação Médica Brasileira (AMB), São Paulo, SP, Brazil
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23
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Moradabadi A, Farsinejad A, Khansarinejad B, Fatemi A. Development of a high resolution melting analysis assay for rapid identification of JAK2 V617F missense mutation and its validation. Exp Hematol Oncol 2019; 8:10. [PMID: 31165012 PMCID: PMC6489328 DOI: 10.1186/s40164-019-0134-0] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2019] [Accepted: 04/20/2019] [Indexed: 01/09/2023] Open
Abstract
Background Myeloproliferative neoplasms (MPN) are heterogeneous diseases that classified by the presence of Philadelphia chromosome into Philadelphia chromosome negative (Ph-neg) and positive (Ph-pos) myeloproliferative neoplasms. In ph-neg group A somatic point mutation (c.1849G>T) in the JAK2 gene, part of the JAK2-STAT signal-transduction pathway, causes substitution of phenylalanine for valine (V617F) in the JAK2 protein and has been identified. This mutation was seen in PV by 65% to 97% and ET (30-57%) and primary myelofibrosis (35-95%). Highly sensitive methods have been used to determine the presence of the JAK2V617F mutation instead of direct sequencing. We aimed to assess JAK2 exon14 mutations by high-resolution melting (HRM) analysis, which allows variation screening in compare to other method for detecting mutation. Methods The mutation analysis included 45 individuals who were subjected for diagnosis of ph-neg MPN. Genomic DNA was isolated and different methods are performed. Results PCR RFLP, ARMS PCR and HRM method has a detection sensitivity comparable with conventional methods (Qiagen) to identify the mutations and sequencing. Conclusions For HRM analysis is cost-effective and beside that it is enzyme independence method also this method able to show amount of the mutant allele carried in samples and it's helpful for treatments follow-up and determining MRD for them.
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Affiliation(s)
- Alireza Moradabadi
- 1Student Research Committee, Faculty of Allied Medicine, Kerman University of Medical Sciences, Kerman, Iran
| | - Alireza Farsinejad
- 2Department of Hematology and Medical Laboratory Sciences, Faculty of Allied Medicine, Kerman University of Medical Sciences, Kerman, Iran
| | - Behzad Khansarinejad
- 3Molecular and Medicine Research Center, Arak University of Medical Sciences, Arak, Iran
| | - Ahamd Fatemi
- 2Department of Hematology and Medical Laboratory Sciences, Faculty of Allied Medicine, Kerman University of Medical Sciences, Kerman, Iran
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24
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Diaz AE, Scherber RM, Mesa RA. Emerging therapies for the treatment of essential thrombocythemia. Expert Opin Orphan Drugs 2018. [DOI: 10.1080/21678707.2018.1520091] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/28/2022]
Affiliation(s)
- Adolfo Enrique Diaz
- Department of Medicine, Division of Hematology-Oncology, Mays Cancer Center at UT Health San Antonio – MD Anderson, San Antonio, TX, USA
| | - Robin M. Scherber
- Department of Medicine, Division of Hematology-Oncology, Mays Cancer Center at UT Health San Antonio – MD Anderson, San Antonio, TX, USA
| | - Ruben A. Mesa
- Department of Medicine, Division of Hematology-Oncology, Mays Cancer Center at UT Health San Antonio – MD Anderson, San Antonio, TX, USA
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25
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Abstract
The emergency providers generally encounters myeloproliferative disorders (MPNs) in 1 of 2 ways: as striking laboratory abnormalities of seeming unknown consequence, or in previously diagnosed patients presenting with complications. The course of patients with MPNs is highly variable, but major complications can arise. Emergent conditions related to hyperviscosity need to be recognized early and treated aggressively. Rapid hydration, transfusion, cytoreduction, and early hematology consultation can be lifesaving. Likewise, although management is not altered, a high index of suspicion for thrombotic complications is required in patients with known MPNs as these are a significant cause of morbidity and mortality.
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26
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Abstract
PURPOSE OF REVIEW Myeloproliferative neoplasms (MPNs) are recognized for their debilitating symptom burdens. The purpose of this review is to understand the complexity of the MPN symptom burden and identify how validated MPN Patient Reported Outcome (PRO) tools may be integrated into clinical practice to assess the MPN symptom burden. RECENT FINDINGS Significant heterogeneity exists both within and between MPN subtypes. Surrogates of disease burden such as risk scores and MPN chronicity often fail to correlate with symptomatic burden. Validated MPN PROs allow for precise and rapid assessment of the MPN symptom burden in clinical and trial settings. Their growing use among investigators has resulted in improved understanding of how the MPN disease burden and overall patient experience is impacted by novel and traditional therapies. PRO tools are an integral part of National Comprehensive Cancer Center (NCCN) guidelines for MPN treatment and should be regularly employed in disease burden assessment.
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Affiliation(s)
- Holly Geyer
- Division of Hospital Internal Medicine, Mayo Clinic, Scottsdale, AZ, USA
| | - Ruben A Mesa
- Division of Hematology and Medical Oncology, Mayo Clinic, 5777 E Mayo Blvd, Phoenix, AZ, 85054, USA.
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27
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Thromboses and hemorrhages are common in MPN patients with high JAK2V617F allele burden. Ann Hematol 2017; 96:1297-1302. [DOI: 10.1007/s00277-017-3040-8] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2017] [Accepted: 05/27/2017] [Indexed: 12/30/2022]
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28
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Assessing the thrombotic risk of patients with essential thrombocythemia in the genomic era. Leukemia 2017; 31:1845-1854. [PMID: 28529308 DOI: 10.1038/leu.2017.150] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2017] [Revised: 04/22/2017] [Accepted: 04/27/2017] [Indexed: 02/07/2023]
Abstract
The molecular characterization of myeloproliferative neoplasms, including essential thrombocythemia (ET), has enabled deeper understanding of their pathogenesis. A driver lesion, namely, Janus kinase (JAK)2V617F, calreticulin (CALR) or myeloproliferative leukemia (MPL) gene mutation can be identified in the vast majority of patients. Each of these mutations is associated with distinct clinical features and may modulate the patients' clinical course, risk of complications, including vascular events, and survival. JAK2V617F appears to be a risk-modifying mutation and has been shown to increase the likelihood of thrombotic events in patients with ET across studies. As such, it has been included in prognostic models and its presence may influence treatment decisions. The association of CALR and MPL mutations with the incidence of vascular events has been less clear. Even more limited information is available on the contribution of additional non-driver lesions to the thrombotic risk. In this review we discuss the available evidence on the role of recurrent mutations in the risk of thrombotic complications in patients with ET and how these mutations weigh into modern prognostic scores.
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29
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Chuzi S, Stein BL. Essential thrombocythemia: a review of the clinical features, diagnostic challenges, and treatment modalities in the era of molecular discovery. Leuk Lymphoma 2017; 58:2786-2798. [DOI: 10.1080/10428194.2017.1312371] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Affiliation(s)
- Sarah Chuzi
- Department of Medicine, Northwestern Feinberg University School of Medicine, Chicago, IL, USA
| | - Brady L. Stein
- Department of Medicine, Northwestern Feinberg University School of Medicine, Chicago, IL, USA
- Robert H. Lurie Comprehensive Cancer Center, Northwestern Feinberg University School of Medicine, Chicago, IL, USA
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30
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Grinfeld J, Godfrey AL. After 10 years of JAK2V617F: Disease biology and current management strategies in polycythaemia vera. Blood Rev 2017; 31:101-118. [DOI: 10.1016/j.blre.2016.11.001] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2016] [Revised: 11/08/2016] [Accepted: 11/14/2016] [Indexed: 12/12/2022]
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31
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Tefferi A, Barbui T. Polycythemia vera and essential thrombocythemia: 2017 update on diagnosis, risk-stratification, and management. Am J Hematol 2017; 92:94-108. [PMID: 27991718 DOI: 10.1002/ajh.24607] [Citation(s) in RCA: 139] [Impact Index Per Article: 17.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2016] [Accepted: 11/11/2016] [Indexed: 12/12/2022]
Abstract
DISEASE OVERVIEW Polycythemia Vera (PV) and essential thrombocythemia (ET) are myeloproliferative neoplasms respectively characterized by erythrocytosis and thrombocytosis; other disease features include leukocytosis, splenomegaly, thrombosis, bleeding, microcirculatory symptoms, pruritus, and risk of leukemic or fibrotic transformation. DIAGNOSIS PV is defined by a JAK2 mutation, whose absence, combined with normal or increased serum erythropoietin level, makes the diagnosis unlikely. JAK2, CALR, and MPL mutations are the mutually exclusive "driver" mutations in ET with respective incidences of 55%, 25%, and 3%; approximately 17% are triple-negative. However, the same molecular markers might also be present in prefibrotic myelofibrosis, whose morphological distinction from ET is prognostically relevant. SURVIVAL AND LEUKEMIC/FIBROTIC TRANSFORMATION Median survivals are approximately 14 years for PV and 20 years for ET; the corresponding values for younger patients (age <60 years) are 24 and 33 years. Life-expectancy in ET is inferior to the control population. Driver mutational status has not been shown to affect survival in ET whereas the presence of JAK2/MPL mutations has been associated with higher risk of arterial thrombosis and that of MPL with higher risk of fibrotic progression. Risk factors for overall survival in both ET and PV include advanced age, leukocytosis and thrombosis. Leukemic transformation rates at 20 years are estimated at <10% for PV and 5% for ET; fibrotic transformation rates are slightly higher. Most recently, ASXL1, SRSF2, and IDH2 mutations have been associated with inferior overall, leukemia-free or fibrosis-free survival in PV; similarly adverse mutations in ET included SH2B3, SF3B1, U2AF1, TP53, IDH2, and EZH2. THROMBOSIS RISK STRATIFICATION Current risk stratification in PV and ET is designed to estimate the likelihood of recurrent thrombosis. Accordingly, PV includes two risk categories: high-risk (age >60 years or thrombosis history) and low-risk (absence of both risk factors). In ET, risk stratification includes four categories: very low risk (age ≤60 years, no thrombosis history, JAK2/MPL un-mutated), low risk (age ≤60 years, no thrombosis history, JAK2/MPL mutated), intermediate risk (age >60 years, no thrombosis history, JAK2/MPL un-mutated), and high risk (thrombosis history or age >60 years with JAK2/MPL mutation). In addition, presence of extreme thrombocytosis (platelets >1000 × 10(9)/L) might be associated with acquired von Willebrand syndrome (AvWS) and, therefore, risk of bleeding. RISK-ADAPTED THERAPY The main goal of therapy in PV and ET is to prevent thrombohemorrhagic complications. All patients with PV require phlebotomy to keep hematocrit below 45% and once-daily aspirin (81 mg). In addition, high-risk patients with PV require cytoreductive therapy. Very low risk ET patients might not require any form of therapy while low-risk patients require at least once-daily aspirin therapy. Cytoreductive therapy is also recommended for high-risk ET patients but it is not mandatory for intermediate-risk patients. First-line drug of choice for cytoreductive therapy, in both ET and PV, is hydroxyurea and second-line drugs of choice are interferon-α and busulfan. We currently do not recommend treatment with ruxolutinib or other JAK2 inhibitors in PV or ET, unless in the presence of severe and protracted pruritus or marked splenomegaly that is not responding to the aforementioned drugs. Screening for AvWS is recommended before administrating aspirin, in the presence of extreme thrombocytosis. Am. J. Hematol. 92:95-108, 2017. © 2016 Wiley Periodicals, Inc.
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Affiliation(s)
- Ayalew Tefferi
- Division of Hematology, Department of Medicine; Mayo Clinic; Rochester Minnesota USA
| | - Tiziano Barbui
- Research Foundation, Papa Giovanni XXIII Hospital; Bergamo Italy
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Moussaoui S, Saussoy P, Ambroise J, Defour JP, Zouitene R, Sifi K, Abadi N. Genetic Risk Factors of Venous Thromboembolism in the East Algerian Population. Clin Appl Thromb Hemost 2016; 23:105-115. [DOI: 10.1177/1076029615600789] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023] Open
Abstract
Many genetic risk factors have been identified for causing venous thromboembolism (VTE). Most of them affect the function of natural anticoagulant pathways, particularly the protein C system, although recent studies suggest a role of components of the hematopoietic pathway in the etiology of venous thrombosis. In this case–control study, we aimed to determine the frequency of prothrombin G20210A and factor V Leiden (FVL) G1691A polymorphisms and protein C, protein S, and antithrombin III deficiencies in the East Algerian population and to investigate whether these genetic factors are associated with VTE. On the other hand, our study tends to evaluate the status of JAK2V617F and calreticulin (CALR) mutations among these cases. The participants consisted of 121 cases with VTE and 146 healthy controls. Polymorphisms of FVL G1691A and prothrombin G20210A were genotyped by polymerase chain reaction (PCR) restriction fragment length polymorphism. JAK2-V617F and calreticulin mutations were analyzed by quantitative PCR and PCR followed by capillary electrophoresis sequencing, respectively. Protein C, protein S, and antithrombin levels were determined and then hereditary deficiencies were identified. Of all cases and controls, none was a carrier of the antithrombin III deficiency, prothrombin gene G20210A, and CALR mutations. Only 1 case reported having a positive JAK2 mutation (mutant allele burden was 15%). The FVL mutation (GA/AA) was found in 14 (11.6%) cases and 2 (1.4%) controls and it was significantly different between both the groups ( P = .001). Deficiencies of protein S and protein C were detected in 17 (18.8%) cases. The univariate analysis resulted in a significant impact of FVL (odds ratio [OR] = 9.4, 95% confidence interval [CI] = 2.1-42.3; P = .003) and of protein S deficiency (OR = 16.9, 95% CI =2.1-132.8, P = .007) on the VTE status. Both factors stayed significant after adjustment for sex and age. The OR of the protein C deficiency was slightly elevated (OR = 6.4, 95% CI = 0.7-55.5), but it did not reach the level of statistical significance ( P = .091), and it was therefore not considered as a risk factor. In conclusion, coagulant factor V gene G1691A mutation and protein S deficiency constitute important genetic risk factors in patients with VTE in Eastern Algeria. The somatic mutation of JAK2 V617F and CALR mutations are less frequent causes of VTE, thus routine testing for these mutations is not recommended.
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Affiliation(s)
- S. Moussaoui
- Laboratoire de recherche en biologie et génétique moléculaire, CHU Dr Benbadis rue Bensghir-Abdelwahed 25000, Constantine, Algeria
- Laboratoire de biochimie, CHU Dr Benbadis rue Bensghir-Abdelwahed 25000, Constantine, Algeria
| | - P. Saussoy
- Laboratoire de biologie moléculaire, cliniques Saint Luc, Université Catholique de Louvain (UCL), Brussels, Belgium
| | - J. Ambroise
- Centres des Technologies Moléculaires Appliquées (CTMA), Institut de Recherche Expérimentale et Clinique (IREC), Université Catholique de Louvain (UCL), Brussels, Belgium
| | - J. P. Defour
- Cliniques Universitaires Saint Luc, Ludwig Institute for Cancer Research, de Duve Institute, Université catholique de Louvain, Brussels, Belgium
| | - R. Zouitene
- Laboratoire d’hémobiologie, hôpital militaire régional universitaire de Constantine, Algeria
| | - K. Sifi
- Laboratoire de recherche en biologie et génétique moléculaire, CHU Dr Benbadis rue Bensghir-Abdelwahed 25000, Constantine, Algeria
- Laboratoire de biochimie, CHU Dr Benbadis rue Bensghir-Abdelwahed 25000, Constantine, Algeria
| | - N. Abadi
- Laboratoire de recherche en biologie et génétique moléculaire, CHU Dr Benbadis rue Bensghir-Abdelwahed 25000, Constantine, Algeria
- Laboratoire de biochimie, CHU Dr Benbadis rue Bensghir-Abdelwahed 25000, Constantine, Algeria
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Yönal İ, Dağlar-Aday A, Akadam-Teker B, Yılmaz C, Nalçacı M, Yavuz AS, Sargın FD. Impact of JAK2V617F Mutational Status on Phenotypic Features in Essential Thrombocythemia and Primary Myelofibrosis. Turk J Haematol 2016; 33:94-101. [PMID: 25913509 PMCID: PMC5100738 DOI: 10.4274/tjh.2014.0136] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023] Open
Abstract
Objective: The JAK2V617F mutation is present in the majority of patients with essential thrombocythemia (ET) and primary myelofibrosis (PMF). The impact of this mutation on disease phenotype in ET and PMF is still a matter of discussion. This study aims to determine whether there are differences in clinical presentation and disease outcome between ET and PMF patients with and without the JAK2V617F mutation. Materials and Methods: In this single-center study, a total of 184 consecutive Philadelphia-negative chronic myeloproliferative neoplasms, 107 cases of ET and 77 cases of PMF, were genotyped for JAK2V617F mutation using the JAK2 Ipsogen MutaScreen assay, which involves allele-specific polymerase chain reaction. Results: ET patients positive for JAK2V617F mutation had higher hemoglobin (Hb) and hematocrit (Hct) levels, lower platelet counts, and more prevalent splenomegaly at diagnosis compared to patients negative for the JAK2V617F mutation, but rates of major thrombotic events, arterial thrombosis, and venous thrombosis were comparable between the groups. At presentation, PMF patients with JAK2V617F mutation had significantly higher Hb and Hct levels and leukocyte counts than patients without the mutation. Similar to the findings of ET patients, thromboembolic rates were similar in PMF patients with and without theJAK2V617F mutation. For ET and PMF patients, no difference was observed in rates of death with respect to JAK2V617F mutational status. Moreover, leukemic transformation rate was not different in our PMF patients with and without JAK2V617F mutation. Conclusion: We conclude that JAK2V617F-mutated ET patients express a polycythemia vera-like phenotype and JAK2V617F mutation in PMF patients is associated with a more pronounced myeloproliferative phenotype.
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Affiliation(s)
- İpek Yönal
- İstanbul University İstanbul Faculty of Medicine, Department of Internal Medicine, Division of Hematology, İstanbul, Turkey, E-mail:
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Andriani A, Latagliata R, Anaclerico B, Spadea A, Rago A, Di Veroli A, Spirito F, Porrini R, De Muro M, Crescenzi Leonetti S, Villivà N, De Gregoris C, Montefusco E, Polverelli N, Santoro C, Breccia M, Cimino G, Majolino I, Mazzucconi MG, Vianelli N, Alimena G, Montanaro M, Palandri F. Spleen enlargement is a risk factor for thrombosis in essential thrombocythemia: Evaluation on 1,297 patients. Am J Hematol 2016; 91:318-21. [PMID: 26748894 DOI: 10.1002/ajh.24269] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2015] [Revised: 11/27/2015] [Accepted: 11/30/2015] [Indexed: 12/31/2022]
Abstract
Spleen enlargement, present in 10-20% of Essential Thrombocythemia (ET) patients at diagnosis, is a feature clinically easy to assess, confirmable by echography with a very low chance of misinterpretation. Nonetheless, the clinical and prognostic role of splenomegaly has been seldom evaluated. From 1979 to 2013, 1297 ET patients retrospectively collected in the database of the Lazio Cooperative Group and Bologna University Hospital were evaluable for spleen enlargement at diagnosis and included in the analysis. On the whole, spleen was enlarged in 172/1297 (13.0%) patients; in most cases (94.8%) splenomegaly was mild (≤5 cm). Patients with splenomegaly were younger, predominantly male, presented higher platelet count and JAK2V617F allele burden and had a lower incidence of concomitant cardiovascular risk factors. At least one thrombotic event during follow-up occurred in 97/1,125 (8.6%) patients without spleen enlargement compared to 27/172 (15.7%) patients with spleen enlargement (P = 0.003). Despite comparable use of cytoreductive/antiplatelet therapies in the two groups, the cumulative risk of thrombosis at 5 years was significantly higher in patients with baseline splenomegaly (9.8% versus 4.4% in patients without splenomegaly, P = 0.012). In multivariate analysis exploring risk factors for thrombosis, splenomegaly retained its negative prognostic role, together with previous thrombosis, leucocyte count and male gender. Baseline splenomegaly seems to be an independent additional risk factor for thrombosis in nonstrictly WHO-defined ET patients. This data could be useful in the real-life clinical management of these patients.
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Affiliation(s)
| | - Roberto Latagliata
- Department of Cellular Biotechnologies and Hematology, University "La Sapienza", Rome
| | | | - Antonio Spadea
- Hematology and Stem Cell Transplantation Unit, Regina Elena National Cancer Institute, Rome
| | - Angela Rago
- Division of Hematology, Polo Universitario Pontino, Latina
| | | | - Francesca Spirito
- Division of Hematology and Bone Marrow Transplantation, Azienda Ospedaliera San Camillo-Forlanini, Rome
| | | | | | | | | | | | | | - Nicola Polverelli
- Institute of Hematology "L. And a. Seràgnoli", Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, S. Orsola-Malpighi Hospital, Italy
| | - Cristina Santoro
- Department of Cellular Biotechnologies and Hematology, University "La Sapienza", Rome
| | - Massimo Breccia
- Department of Cellular Biotechnologies and Hematology, University "La Sapienza", Rome
| | | | - Ignazio Majolino
- Division of Hematology and Bone Marrow Transplantation, Azienda Ospedaliera San Camillo-Forlanini, Rome
| | | | - Nicola Vianelli
- Institute of Hematology "L. And a. Seràgnoli", Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, S. Orsola-Malpighi Hospital, Italy
| | - Giuliana Alimena
- Department of Cellular Biotechnologies and Hematology, University "La Sapienza", Rome
| | | | - Francesca Palandri
- Institute of Hematology "L. And a. Seràgnoli", Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, S. Orsola-Malpighi Hospital, Italy
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Tefferi A. Myeloproliferative neoplasms: A decade of discoveries and treatment advances. Am J Hematol 2016; 91:50-8. [PMID: 26492355 DOI: 10.1002/ajh.24221] [Citation(s) in RCA: 110] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2015] [Accepted: 10/19/2015] [Indexed: 12/14/2022]
Abstract
Myeloproliferative neoplasms (MPN) are clonal stem cell diseases, first conceptualized in 1951 by William Dameshek, and historically included chronic myeloid leukemia (CML), polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). In 1960, Nowell and Hungerford discovered an invariable association between the Philadelphia chromosome (subsequently shown to harbor the causal BCR-ABL1 mutation) and CML; accordingly, the term MPN is primarily reserved for PV, ET, and PMF, although it includes other related clinicopathologic entities, according to the World Health Organization (WHO) classification system. In 2005, William Vainchenker and others described a Janus kinase 2 mutation (JAK2V617F) in MPN and this was followed by a series of additional descriptions of mutations that directly or indirectly activate JAK-STAT: JAK2 exon 12, myeloproliferative leukemia virus oncogene (MPL) and calreticulin (CALR) mutations. The discovery of these, mostly mutually exclusive, "driver" mutations has contributed to revisions of the WHO diagnostic criteria and risk stratification in MPN. Mutations other than JAK2, CALR and MPL have also been described in MPN and shown to provide additional prognostic information. From the standpoint of treatment, over the last 50 years, Louis Wasserman from the Unites States and Tiziano Barbui from Italy had skillfully organized and led a number of important clinical trials, whose results form the basis for current treatment strategies in MPN. More recently, allogeneic stem cell transplant, as a potentially curative treatment modality, and JAK inhibitors, as palliative drugs, have been added to the overall therapeutic armamentarium in myelofibrosis. In the current review, I will summarize the important advances made in the last 10 years regarding the science and practice of MPN.
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Affiliation(s)
- Ayalew Tefferi
- Division of Hematology, Department of Medicine; Mayo Clinic; Rochester Minnesota
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Abstract
Essential thrombocythemia patients develop acute myeloid leukemia (AML) at a rate of 1-4% during a median follow-up of 7-10 years. The risk increases with advanced age, anemia, platelet count ≥ 1000 × 10(9)/l, the presence of ≥ 2 somatic mutations and after the first decade of diagnosis. The use of alkylating agents and (32)radiophosphorus, particularly in higher doses, but not hydroxyurea and anagrelide, increases the risk. AML in essential thrombocythemia patients is frequently associated with unfavorable cytogenetics and poor prognosis. In young and fit patients, AML-type induction chemotherapy followed by allogeneic stem cell transplantation may offer the best chance of long-term disease control. In select elderly patients with poor performance status, hypomethylating agent such as azacytidine may prolong survival.
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Michiels JJ, Valster F, Wielenga J, Schelfout K, Raeve HD. European vs 2015-World Health Organization clinical molecular and pathological classification of myeloproliferative neoplasms. World J Hematol 2015; 4:16-53. [DOI: 10.5315/wjh.v4.i3.16] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2014] [Revised: 11/15/2014] [Accepted: 04/30/2015] [Indexed: 02/05/2023] Open
Abstract
The BCR/ABL fusion gene or the Ph1-chromosome in the t(9;22)(q34;q11) exerts a high tyrokinase acticity, which is the cause of chronic myeloid leukemia (CML). The 1990 Hannover Bone Marrow Classification separated CML from the myeloproliferative disorders essential thrombocythemia (ET), polycythemia vera (PV) and chronic megakaryocytic granulocytic myeloproliferation (CMGM). The 2006-2008 European Clinical Molecular and Pathological (ECMP) criteria discovered 3 variants of thrombocythemia: ET with features of PV (prodromal PV), “true” ET and ET associated with CMGM. The 2008 World Health Organization (WHO)-ECMP and 2014 WHO-CMP classifications defined three phenotypes of JAK2V617F mutated ET: normocellular ET (WHO-ET), hypercelluar ET due to increased erythropoiesis (prodromal PV) and ET with hypercellular megakaryocytic-granulocytic myeloproliferation. The JAK2V617F mutation load in heterozygous WHO-ET is low and associated with normal life expectance. The hetero/homozygous JAK2V617F mutation load in PV and myelofibrosis is related to myeloproliferative neoplasm (MPN) disease burden in terms of symptomatic splenomegaly, constitutional symptoms, bone marrow hypercellularity and myelofibrosis. JAK2 exon 12 mutated MPN presents as idiopathic eryhrocythemia and early stage PV. According to 2014 WHO-CMP criteria JAK2 wild type MPL515 mutated ET is the second distinct thrombocythemia featured by clustered giant megakaryocytes with hyperlobulated stag-horn-like nuclei, in a normocellular bone marrow consistent with the diagnosis of “true” ET. JAK2/MPL wild type, calreticulin mutated hypercellular ET appears to be the third distinct thrombocythemia characterized by clustered larged immature dysmorphic megakaryocytes and bulky (bulbous) hyperchromatic nuclei consistent with CMGM or primary megakaryocytic granulocytic myeloproliferation.
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Stein H, Bob R, Dürkop H, Erck C, Kämpfe D, Kvasnicka HM, Martens H, Roth A, Streubel A. A new monoclonal antibody (CAL2) detects CALRETICULIN mutations in formalin-fixed and paraffin-embedded bone marrow biopsies. Leukemia 2015. [PMID: 26202929 PMCID: PMC4705422 DOI: 10.1038/leu.2015.192] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
Recent advances in the diagnostic of myeloproliferative neoplasms (MPNs) discovered CALRETICULIN (CALR) mutations as a major driver in these disorders. In contrast to JAK2 mutations being mainly associated with polycythaemia vera, CALR mutations are only associated with primary myelofibrosis (PMF) and essential thrombocythaemia (ET). CALR mutations are present in the majority of PMF and ET patients lacking JAK2 and MPL mutations. As these CALR mutations are absent from reactive bone marrow (BM) lesions their presence indicates ET or PMF. So far these mutations are detectable only by molecular assays. Their molecular detection is cumbersome because of the great CALR mutation heterogeneity. Therefore, the availability of a simple assay would be of great help. All CALR mutations reported lead to a frameshift generating a new 36 amino-acid C-terminus. We generated a monoclonal antibody (CAL2) to this C-neoterminus by immunizing mice with a representative peptide and compared its performance with Sanger sequencing data in 173 MPNs and other BM diseases. There was a 100% correlation between the molecular and the CAL2 immunohistochemical (IHC) assays. Thus, the detection of CALR mutations by the CAL2 IHC is a specific, sensitive, rapid, simple and low-cost method.
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Affiliation(s)
- H Stein
- Reference and Consultation Center for Lymphoma and Haematopathology, Pathodiagnostik Berlin, Berlin, Germany
| | - R Bob
- Reference and Consultation Center for Lymphoma and Haematopathology, Pathodiagnostik Berlin, Berlin, Germany
| | - H Dürkop
- Reference and Consultation Center for Lymphoma and Haematopathology, Pathodiagnostik Berlin, Berlin, Germany
| | - C Erck
- Synaptic Systems GmbH, Göttingen, Germany
| | - D Kämpfe
- Praxis für Onkologie, Lüdenscheid, Germany
| | - H-M Kvasnicka
- Senckenbergisches Institut für Pathologie, Johann Wolfgang Goethe-Universität, Frankfurt am Main, Germany
| | - H Martens
- Synaptic Systems GmbH, Göttingen, Germany
| | - A Roth
- Medizinisches Versorgungszentrum am Helios Klinikum Emil von Behring, Labor für molekulare Diagnostik und Mikrobiologie, Berlin, Germany
| | - A Streubel
- Medizinisches Versorgungszentrum am Helios Klinikum Emil von Behring, Labor für molekulare Diagnostik und Mikrobiologie, Berlin, Germany
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Sevindik OG, Mersin S, Katgi A, Tunali S, Solmaz SM, Acar C, Alacacioglu I, Piskin O, Ozcan MA, Demirkan F, Undar B, Ozsan GH. IPSET-Thrombosis Better Identifies Thrombosis-Free Survival: A Turkish Cohort. CLINICAL LYMPHOMA MYELOMA & LEUKEMIA 2015; 15:e101-4. [DOI: 10.1016/j.clml.2015.02.004] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/29/2014] [Revised: 01/09/2015] [Accepted: 02/03/2015] [Indexed: 11/27/2022]
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Al Assaf C, Van Obbergh F, Billiet J, Lierman E, Devos T, Graux C, Hervent AS, Emmerechts J, Tousseyn T, De Paepe P, Papadopoulos P, Michaux L, Vandenberghe P. Analysis of phenotype and outcome in essential thrombocythemia with CALR or JAK2 mutations. Haematologica 2015; 100:893-7. [PMID: 25934766 DOI: 10.3324/haematol.2014.118299] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2014] [Accepted: 04/27/2015] [Indexed: 11/09/2022] Open
Abstract
The JAK2 V617F mutation, the thrombopoietin receptor MPL W515K/L mutation and calreticulin (CALR) mutations are mutually exclusive in essential thrombocythemia and support a novel molecular categorization of essential thrombocythemia. CALR mutations account for approximately 30% of cases of essential thrombocythemia. In a retrospective study, we examined the frequency of MPL and CALR mutations in JAK2 V617F-negative cases of essential thrombocythemia (n=103). In addition, we compared the clinical phenotype and outcome of CALR mutant cases of essential thrombocythemia with a cohort of JAK2 V617F-positive essential thrombocythemia (n=57). CALR-positive cases represented 63.7% of double-negative cases of essential thrombocythemia, and most carried CALR type 1 or type 2 indels. However, we also identified one patient who was positive for both the JAK2 V617F and the CALR mutations. This study revealed that CALR mutant essential thrombocythemia is associated with younger age, higher platelet counts, lower erythrocyte counts, leukocyte counts, hemoglobin, and hematocrit, and increased risk of progression to myelofibrosis in comparison with JAK2 V617F-positive essential thrombocythemia. Analysis of the CALR mutant group according to indel type showed that CALR type 1 deletion is strongly associated with male gender. CALR mutant patients had a better overall survival than JAK2 V617F-positive patients, in particular patients of age 60 years or younger. In conclusion, this study in a Belgian cohort of patients supports and extends the growing body of evidence that CALR mutant cases of essential thrombocythemia are phenotypically distinct from JAK2 V617F-positive cases, with regards to clinical and hematologic presentation as well as overall survival.
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Affiliation(s)
- Carla Al Assaf
- Center for Human Genetics, KU Leuven and University Hospitals Leuven, Belgium
| | | | | | - Els Lierman
- Center for Human Genetics, KU Leuven and University Hospitals Leuven, Belgium
| | - Timothy Devos
- Department of Hematology, University Hospitals Leuven, Belgium
| | - Carlos Graux
- Department of Hematology, Mont-Godinne University Hospital, Yvoir, Belgium
| | | | | | - Thomas Tousseyn
- Department of Pathology, University Hospitals Leuven, Belgium
| | | | - Petros Papadopoulos
- Center for Human Genetics, KU Leuven and University Hospitals Leuven, Belgium
| | - Lucienne Michaux
- Center for Human Genetics, KU Leuven and University Hospitals Leuven, Belgium
| | - Peter Vandenberghe
- Center for Human Genetics, KU Leuven and University Hospitals Leuven, Belgium Department of Hematology, University Hospitals Leuven, Belgium
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Zhang X, Zhou M, Chao H, Lu X, Cen L. [CALR gene mutation detection and clinical observation of 150 essential thrombocythemia patients]. ZHONGHUA XUE YE XUE ZA ZHI = ZHONGHUA XUEYEXUE ZAZHI 2015; 36:378-82. [PMID: 26031522 PMCID: PMC7342596 DOI: 10.3760/cma.j.issn.0253-2727.2015.05.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/14/2014] [Indexed: 11/19/2022]
Abstract
OBJECTIVE To explore the prevalence of CARL gene mutations and the mutation types in patients with essential thrombocythemia (ET), and to compare the patients clinical characteristics of CALR mutation with JAK2 V617F, MPL W515K mutation patients and triple negative group. METHODS The mutations of CALR gene at extron 9 and MPL W515K in 150 ET patients were detected by PCR amplification followed by direct sequencing of genomic DNA, the JAK2 V617F mutation by using allele specific PCR. RESULTS (1)The CALR mutations were found in 38 patients (25.3%) of 150 ET patients. A total of 4 types of CALR mutations were identified (type Ic.1092_1143del52bp, n=17; type II c.1154_1155insTTGTC, n=16; type III c.1094_1139del46bp, n=4; type IV c.1103_1136del34bp, n=1). (2)The incidence of JAK2 V617F and MPL W515K was 61.3% (92/150) and 2.7% (4/150), respectively. The frequency of CALR mutation was 70.4% (38/54) in 54 ET patients without JAK2 V617F and MPL W515K mutations. The co-occurrence of any two kinds of gene mutations was not detected. (3)The hemoglobin level and leukocyte counts of patients with CARL mutations were significantly lower than that in patients with JAK2 V617F mutations (P<0.05). The median age of patients with CALR mutation was significantly higher than that of triple negative patients (59 years vs 29.5 years, P<0.01). Cytogenetic analysis was performed in 147 patients, and there were 4 abnormal karyotype cases. CALR mutation incidence was significantly higher in abnormal karyotype cases than that in normal ones (75% vs 24.5%, P=0.019). CONCLUSION The incidence of CALR mutations is high in ET patients without JAK2 V617F and MPL W515K mutations, and is associated with abnormal karyotype. CARL-mutated cases showed a significantly lower leucocyte and hemoglobin levels compared with JAK2 V617F mutated cases.
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Affiliation(s)
- Xiuwen Zhang
- Department of Hematology, the Affiliated Hospital of Nanjing Medical University, Changzhou No.2 People's Hospital, Changzhou 213003, China
| | - Min Zhou
- Department of Hematology, the Affiliated Hospital of Nanjing Medical University, Changzhou No.2 People's Hospital, Changzhou 213003, China
| | - Hongying Chao
- Department of Hematology, the Affiliated Hospital of Nanjing Medical University, Changzhou No.2 People's Hospital, Changzhou 213003, China
| | - Xuzhang Lu
- Department of Hematology, the Affiliated Hospital of Nanjing Medical University, Changzhou No.2 People's Hospital, Changzhou 213003, China
| | - Ling Cen
- Department of Hematology, the Affiliated Hospital of Nanjing Medical University, Changzhou No.2 People's Hospital, Changzhou 213003, China
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JAK2V617F: Is It Sufficient as a Single Player in Splanchnic Venous Thrombosis? Case Rep Hematol 2015; 2015:373490. [PMID: 25878908 PMCID: PMC4387965 DOI: 10.1155/2015/373490] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2015] [Revised: 03/12/2015] [Accepted: 03/12/2015] [Indexed: 12/12/2022] Open
Abstract
Splanchnic venous thrombosis (SVT) includes thrombosis of the hepatic, portal, and mesenteric venous system. Myeloproliferative neoplasms (MPNs) are important factors of SVT in adults. Addition of JAK2V617F mutation in WHO criteria for diagnosis of MPNs has made this test a useful tool for diagnosis. JAK2 is an intracytoplasmic tyrosine kinase that plays a critical role in signal transduction from multiple hematopoietic factor receptors. The mutation is found frequently in patients with SVT; many such patients have no other manifestations of an MPN. Although the correlation of JAK2V617F mutation with thrombotic risk in MPNs has been shown in many studies, the impact of presence of additional thrombophilic factors in these cases is yet not known. As the management of MPNs remains highly dependent on the patient's thrombotic risk, it is important to assess the thrombotic risk factors in detail. Here, we report two cases of JAK2V617F positive MPN who also had other thrombophilic conditions and presented with recurrent thrombosis.
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Tefferi A, Barbui T. Polycythemia vera and essential thrombocythemia: 2015 update on diagnosis, risk-stratification and management. Am J Hematol 2015; 90:162-73. [PMID: 25611051 DOI: 10.1002/ajh.23895] [Citation(s) in RCA: 146] [Impact Index Per Article: 14.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2014] [Accepted: 11/05/2014] [Indexed: 12/12/2022]
Abstract
DISEASE OVERVIEW Polycythemia vera (PV) and essential thrombocythemia (ET) are myeloproliferative neoplasms, respectively characterized by erythrocytosis and thrombocytosis. Other disease features include leukocytosis, splenomegaly, thrombosis, bleeding, microcirculatory symptoms, pruritus, and risk of leukemic or fibrotic transformation. DIAGNOSIS PV is defined by a JAK2 mutation, whose absence, combined with normal or increased serum erythropoietin level, makes the diagnosis unlikely. Differential diagnosis in ET includes reactive thrombocytosis, chronic myeloid leukemia, and prefibrotic myelofibrosis. Janus kinase 2 (JAK2), calreticulin (CALR), or myeloproliferative leukemia virus oncogene (MPL) mutations occur in approximately 55%, 25%, and 3% of ET patients, respectively. The same molecular markers are also present in prefibrotic myelofibrosis, which needs to be morphologically distinguished from ET. Survival and leukemic/fibrotic transformation: Median survivals are ∼14 years for PV and 20 years for ET; the corresponding values for younger patients are 24 and 33 years. Life-expectancy in ET is inferior to the control population. JAK2/CALR mutational status does not affect survival in ET. Risk factors for survival in ET and PV include advanced age, leukocytosis, and thrombosis. Leukemic transformation rates at 20 years are estimated at <10% for PV and 5% for ET; fibrotic transformation rates are slightly higher. Thrombosis risk stratification: Current risk stratification in PV and ET is designed to estimate the likelihood of recurrent thrombosis: high-risk is defined by the presence of age >60 years or presence of thrombosis history; low-risk is defined by the absence of both of these two risk factors. Recent data consider JAK2V617F and cardiovascular risk factors as additional risk factors. Presence of extreme thrombocytosis might be associated with acquired von Willebrand syndrome (AvWS) and, therefore, risk of bleeding. RISK-ADAPTED THERAPY The main goal of therapy in PV and ET is to prevent thrombohemorrhagic complications. In low risk patients, this is accomplished by the use of low-dose aspirin and phlebotomy (hematocrit target <45%) in PV. In high risk (for thrombosis) patients, treatment with hydroxyurea is additionally recommended. Treatment with busulfan or interferon-α is usually effective in hydroxyurea failures and the additional value of JAK inhibitor therapy in such cases is limited. Screening for AvWS is recommended before administrating aspirin, in the presence of extreme thrombocytosis.
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Affiliation(s)
- Ayalew Tefferi
- Division of Hematology, Department of Medicine; Mayo Clinic; Rochester Minnesota
| | - Tiziano Barbui
- Research Foundation; Papa Giovanni XXIII Hospital; Bergamo Italy
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Angona A, Alvarez-Larrán A, Bellosillo B, Martínez-Avilés L, Garcia-Pallarols F, Longarón R, Ancochea À, Besses C. [Essential thrombocythemia: baseline characteristics and risk factors for survival and thrombosis in a series of 214 patients]. Med Clin (Barc) 2014; 144:247-53. [PMID: 25192581 DOI: 10.1016/j.medcli.2014.04.029] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2014] [Revised: 04/22/2014] [Accepted: 04/24/2014] [Indexed: 10/24/2022]
Abstract
BACKGROUND AND OBJECTIVE Two prognostic models to predict overall survival and thrombosis-free survival have been proposed: International Prognostic Score for Essential Thrombocythemia (IPSET) and IPSET-Thrombosis, respectively, based on age, leukocytes count, history of previous thrombosis, the presence of cardiovascular risk factors and the JAK2 mutational status. The aim of the present study was to assess the clinical and biological characteristics at diagnosis and during evolution in essential thrombocythemia (ET) patients as well as the factors associated with survival and thrombosis and the usefulness of these new prognostic models. PATIENTS AND METHODS We have evaluated the clinical data and the mutation status of JAK2, MPL and calreticulin of 214 ET patients diagnosed in a single center between 1985 and 2012, classified according to classical risk stratification, IPSET and IPSET-Thrombosis. RESULTS With a median follow-up of 6.9 years, overall survival was not associated with any variable by multivariate analysis. Thrombotic history and leukocytes>10×10(9)/l were associated with thrombosis-free survival (TFS). In our series, IPSET prognostic systems of survival and thrombosis did not provide more clinically relevant information regarding the classic risk of thrombosis stratification. CONCLUSION Thrombotic history and leukocytosis>10×10(9)/l were significantly associated with lower TFS, while the prognostic IPSET-Thrombosis system did not provide more information than classical thrombotic risk assessment.
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Affiliation(s)
- Anna Angona
- Servicio de Hematología, Hospital del Mar-IMIM, Barcelona, España; Universitat Autònoma de Barcelona, Barcelona, España; Grup de Recerca Clínica Aplicada en Neoplàsies Hematològiques, Hospital del Mar-IMIM, Barcelona, España
| | - Alberto Alvarez-Larrán
- Servicio de Hematología, Hospital del Mar-IMIM, Barcelona, España; Universitat Autònoma de Barcelona, Barcelona, España; Grup de Recerca Clínica Aplicada en Neoplàsies Hematològiques, Hospital del Mar-IMIM, Barcelona, España
| | - Beatriz Bellosillo
- Grup de Recerca Clínica Aplicada en Neoplàsies Hematològiques, Hospital del Mar-IMIM, Barcelona, España; Servicio de Patología, Hospital del Mar-IMIM, Barcelona, España; Universitat Pompeu Fabra, Barcelona, España
| | - Luz Martínez-Avilés
- Universitat Autònoma de Barcelona, Barcelona, España; Grup de Recerca Clínica Aplicada en Neoplàsies Hematològiques, Hospital del Mar-IMIM, Barcelona, España; Servicio de Patología, Hospital del Mar-IMIM, Barcelona, España
| | - Francesc Garcia-Pallarols
- Servicio de Hematología, Hospital del Mar-IMIM, Barcelona, España; Grup de Recerca Clínica Aplicada en Neoplàsies Hematològiques, Hospital del Mar-IMIM, Barcelona, España
| | - Raquel Longarón
- Grup de Recerca Clínica Aplicada en Neoplàsies Hematològiques, Hospital del Mar-IMIM, Barcelona, España; Servicio de Patología, Hospital del Mar-IMIM, Barcelona, España
| | - Àgueda Ancochea
- Servicio de Hematología, Hospital del Mar-IMIM, Barcelona, España; Universitat Autònoma de Barcelona, Barcelona, España; Grup de Recerca Clínica Aplicada en Neoplàsies Hematològiques, Hospital del Mar-IMIM, Barcelona, España
| | - Carles Besses
- Servicio de Hematología, Hospital del Mar-IMIM, Barcelona, España; Grup de Recerca Clínica Aplicada en Neoplàsies Hematològiques, Hospital del Mar-IMIM, Barcelona, España.
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Michiels JJ, Berneman Z, Schroyens W, De Raeve H. Changing concepts of diagnostic criteria of myeloproliferative disorders and the molecular etiology and classification of myeloproliferative neoplasms: from Dameshek 1950 to Vainchenker 2005 and beyond. Acta Haematol 2014; 133:36-51. [PMID: 25116092 DOI: 10.1159/000358580] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2013] [Accepted: 01/10/2014] [Indexed: 12/23/2022]
Abstract
The Polycythemia Vera Study Group (PVSG) and WHO classifications distinguished the Philadelphia (Ph(1)) chromosome-positive chronic myeloid leukemia from the Ph(1)-negative myeloproliferative neoplasms (MPN) essential thrombocythemia (ET), polycythemia vera (PV) and primary myelofibrosis (MF) or primary megakaryocytic granulocytic myeloproliferation (PMGM). Half of PVSG/WHO-defined ET patients show low serum erythropoietin levels and carry the JAK2(V617F) mutation, indicating prodromal PV. The positive predictive value of a JAK2(V617F) PCR test is 95% for the diagnosis of PV, and about 50% for ET and MF. The WHO-defined JAK2(V617F)-positive ET comprises three ET phenotypes at clinical and bone marrow level when the integrated WHO and European Clinical, Molecular and Pathological (ECMP) criteria are applied: normocellular ET (WHO-ET), hypercellular ET due to increased erythropoiesis (prodromal PV) and hypercellular ET associated with megakaryocytic granulocytic myeloproliferation (EMGM). Four main molecular types of clonal MPN can be distinguished: JAK2(V617F)-positive ET and PV; JAK2 wild-type ET carrying the MPL(515); mutations in the calreticulin (CALR) gene in JAK2/MPL wild-type ET and MF, and a small proportion of JAK2/MPL/CALR wild-type ET and MF patients. The JAK2(V617F) mutation load is low in heterozygous normocellular WHO-ET. The JAK2(V617F) mutation load in hetero-/homozygous PV and EMGM is clearly related to MPN disease burden in terms of splenomegaly, constitutional symptoms and fibrosis. The JAK2 wild-type ET carrying the MPL(515) mutation is featured by clustered small and giant megakaryocytes with hyperlobulated stag-horn-like nuclei, in a normocellular bone marrow (WHO-ET), and lacks features of PV. JAK2/MPL wild-type, CALR mutated hypercellular ET associated with PMGM is featured by dense clustered large immature dysmorphic megakaryocytes and bulky (cloud-like) hyperchromatic nuclei, which are never seen in WHO-ECMP-defined JAK2(V617F) mutated ET, EMGM and PV, and neither in JAK2 wild-type ET carrying the MPL(515) mutation. Two thirds of JAK2/MPL wild-type ET and MF patients carry one of the CALR mutations as the cause of the third distinct MPN entity. WHO-ECMP criteria are recommended to diagnose, classify and stage the broad spectrum of MPN of various molecular etiologies.
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Pieri L, Guglielmelli P, Finazzi G, Vannucchi AM. Givinostat for the treatment of polycythemia vera. Expert Opin Orphan Drugs 2014. [DOI: 10.1517/21678707.2014.934223] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
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Abstract
The emergency providers generally encounters myeloproliferative disorders (MPNs) in 1 of 2 ways: as striking laboratory abnormalities of seeming unknown consequence, or in previously diagnosed patients presenting with complications. The course of patients with MPNs is highly variable, but major complications can arise. Emergent conditions related to hyperviscosity need to be recognized early and treated aggressively. Rapid hydration, transfusion, cytoreduction, and early hematology consultation can be lifesaving. Likewise, although management is not altered, a high index of suspicion for thrombotic complications is required in patients with known MPNs as these are a significant cause of morbidity and mortality.
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Affiliation(s)
- Brian Meier
- Department of Emergency Medicine, Carilion Clinic, 525 Janette Avenue Southwest, Roanoke, VA 24016, USA
| | - John H Burton
- Department of Emergency Medicine, Carilion Clinic, PO Box 13367, Roanoke, VA 24033, USA.
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Geyer H, Mesa RA. Assessing disease burden in patients with classic MPNs. Best Pract Res Clin Haematol 2014; 27:107-19. [DOI: 10.1016/j.beha.2014.07.006] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2014] [Accepted: 07/11/2014] [Indexed: 01/26/2023]
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It is time to change thrombosis risk assessment for PV and ET? Best Pract Res Clin Haematol 2014; 27:121-7. [DOI: 10.1016/j.beha.2014.07.005] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2014] [Accepted: 07/11/2014] [Indexed: 01/08/2023]
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Payzin KB, Savasoglu K, Alacacioglu I, Ozdemirkiran F, Mutlu BB, Bener S, Calli AO, Kucukzeybek BB, Aksun S. JAK2 V617F mutation status of 232 patients diagnosed with chronic myeloproliferative neoplasms. CLINICAL LYMPHOMA MYELOMA & LEUKEMIA 2014; 14:525-33. [PMID: 24811089 DOI: 10.1016/j.clml.2014.02.013] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/28/2014] [Revised: 02/19/2014] [Accepted: 02/24/2014] [Indexed: 01/30/2023]
Abstract
INTRODUCTION/BACKGROUND The aim of this study was to investigate the presence of Janus kinase 2 (JAK2) V617F mutation in patients with break point cluster region-abelson negative chronic myeloproliferative neoplasms (CMPNs) in our center. PATIENTS AND METHODS We compared patients with and without the mutation, and also patients with the homozygous and heterozygous mutation, in terms of different clinical and laboratory features. RESULTS The JAK2 V617F mutation was detected in 77 (95%), 88 (68%), and 17 (77%) of polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF) patients, respectively. Among JAK2 V617F-positive patients, the homozygous genotype was found in 39 (50.6%) of the 77 PV, 23 (26.1%) of the 88 ET, and 11 (64.7%) of the 17 PMF patients. Bleeding was seen in 14 (6%) of all patients. Upper gastrointestinal bleeds were the most common, seen in 11 patients. Out of 232 CMPN patients, 44 (19%) had thrombosis. The most common thrombotic event was transient ischemic attack (52%). Progression to myelofibrosis was seen in 1 (1.2%) PV and 3 (2.3%) ET patients, and progression to acute leukemia was seen in 2 (2.5%) PV and 3 (2.3%) ET patients. Three patients with PV (3.7%), 3 with ET (2.7%), and 5 with PMF (2.7%) died during follow-up. CONCLUSION JAK2 V617F mutation frequencies in our PV and ET patients were similar to those reported previously. JAK2 V617F mutation frequency in our PMF patients was greater than in previous reports. All of our PV patients with thrombosis and most of our ET patients with thrombosis (76.1%) were JAK2 V617F mutation-positive. This mutation seems to be correlated with thrombosis risk.
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Affiliation(s)
- Kadriye Bahriye Payzin
- Division of Hematology, Department of Internal Medicine, Ataturk Training Hospital, Izmir, Turkey.
| | - Kaan Savasoglu
- Medical Genetics Laboratory, Ataturk Training Hospital, Izmir, Turkey
| | - Inci Alacacioglu
- Department of Hematology, Dokuz Eylul University Faculty of Medicine, Izmir, Turkey
| | - Fusun Ozdemirkiran
- Division of Hematology, Department of Internal Medicine, Ataturk Training Hospital, Izmir, Turkey
| | | | - Sadi Bener
- Department of Pathology, Ataturk Training Hospital, Izmir, Turkey
| | | | | | - Saliha Aksun
- Department of Biochemistry, Ataturk Training Hospital, Izmir, Turkey
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