Clinical significance of the transcription factor (SOX11) expression in the bone marrow of acute myeloid leukemia patients

Abstract

BACKGROUND

The prognosis for acute myeloid leukemia (AML) remains poor, underscoring the need for a deeper understanding of its underlying molecular mechanisms.

AIM

To assess the significance of SOX11 gene expression in the clinical features, response to treatment, and survival outcomes of adult patients with AML.

METHODS

This retrospective study enrolled 102 adults with AML. SOX11 gene expression in bone marrow samples was measured using real-time PCR. Data were correlated to the patients’ clinical features, response to treatment, and survival rates.

RESULTS

Increased SOX11 expression was significantly associated with the presence of the FLT3-ITD mutation (P < 0.001), the FAB-M2 subtype (P = 0.008), and cytogenetic abnormalities (P = 0.011). However, no significant association was found between SOX11 expression and other clinical laboratory parameters, complete remission, disease-free survival, or overall survival.

CONCLUSION

SOX11 expression may serve as a marker to identify specific subsets of AML patients who could benefit from intensive targeted chemotherapy.

Key Words: Acute myeloid leukemia; SOX11; FLT3; Gene expression; Real-time PCR

Core Tip: Higher SOX11 expression correlated with FAB M2 and abnormal cytogenetics in acute myeloid leukemia (AML) patients. The association of higher SOX11 expression with the FLT-ITD mutation could be useful in identifying high-risk AML patients who may benefit from targeted or more intensive therapies. Furthermore, the association of higher SOX11 expression with cytogenetic abnormalities might have implications in predicting risk of translocation development and relapse in patients undertaking high risk therapy.

INTRODUCTION

Acute myeloid leukemia (AML) is a highly aggressive hematological malignancy characterized by uncontrolled proliferation and impaired differentiation of leukemic precursor cells in the bone marrow (BM), peripheral blood, or other organs. It arises from the suppression of normal marrow components. AML is characterized by significant variability in morphological features, cytogenetic and molecular profiles, and clinical outcomes[1]. Unfortunately, therapeutic responses in AML have been suboptimal, with a high mortality rate, particularly among elderly patients and those with relapsed or refractory disease. In addition, despite intensive chemotherapy, hematopoietic stem cell transplantation, and emerging targeted therapies, the incidence of relapse remains high. Therefore, the identification of new reliable molecular markers remains essential for precise prognostication and individualized therapy[2,3]. Recent studies have increasingly focused on the role of transcription factors (TFs) in cancer pathogenesis. In particular, the dysregulation of genes encoding TFs, including those in the SOX family, has been reported in various malignancies[4]. The SOX gene family comprises more than 20 transcription factors among 9 groups (group A, B1, B2, C-H), which share a conserved HMG box domain that is highly similar to the domain found in the sex-determining region on the Y chromosome. This domain is critical for mediating their functional interactions and nuclear transport[5]. They regulate various biological processes during embryonic development and are involved in cancer initiation and progression by controlling cell fate and differentiation[6]. SOX11 is a member of the Sox C group of transcription factors, along with SOX4 and SOX12. SOX11 is highly expressed in the fetal central and peripheral nervous systems, along with specific epithelial tissues, including renal, pulmonary, and alimentary tract, as well as in the spleen and the gonads[7,8]. SOX11 knockout mice exhibit significant organ hypoplasia and malformations, such as cardiac, pulmonary, gastric, renal, and vascular defects, indicating that SOX11 is vital during embryogenesis[9,10]. However, SOX11 expression decreases throughout development until it becomes undetectable in adult tissues, indicating its crucial role during early developmental and differentiation processes[11]. The re-expression of SOX11 has been reported in various cancers, exhibiting variable expression patterns across different malignant tumors, which may contribute to diagnosis, prognosis, and treatment decision-making. For example, high SOX11 mRNA levels were detected in many solid tumors and hematopoietic malignancies, including breast cancer[12], hepatocellular and pancreatic carcinomas[13,14], mantle cell lymphoma (MCL), Burkitt lymphoma and subsets of B-cell acute lymphoblastic leukemia (B-ALL)[8,15]. In contrast, low SOX11 expression has been reported in other cancers, such as prostatic, gastric, and bladder carcinomas and diffuse large B-cell lymphoma[16-19]. Increased SOX11 expression is associated with worse survival and poor prognosis in breast cancer and chronic lymphocytic leukemia (CLL)[12,20], whereas it is associated with improved survival and prognosis in B-ALL[8]. In MCL, nuclear SOX11 expression serves as a diagnostic marker; however, its expression has been associated with both favorable and unfavorable prognoses[21,22]. Therapeutic targeting of the SOX11 gene in endometrial cancer using micro-RNA (miR-145) reduced its expression and inhibited cancer cell spread and metastasis[23]. Although previous studies have suggested that increased SOX11 expression negatively impacts the survival of AML patients, such studies were limited by small sample sizes, and their findings require further validation[24]. There is limited understanding of the SOX11’s role in AML pathogenesis and prognosis. In this study, we measured SOX11 gene expression in de-novo adult AML patients to correlate its levels with established prognostic parameters, treatment response, and clinical outcomes. This study also aims to validate the potential of SOX11 as a prognostic molecular biomarker in AML.

MATERIALS AND METHODS

This retrospective study included samples from 102 adults diagnosed with AML who received treatment at the National Cancer Institute (NCI), Cairo University, between March 2018 and December 2020. Samples were collected following diagnosis and prior to the initiation of any treatment. The diagnosis of AML was established via clinical examination and BM assessment, including cytomorphological, cytochemical, and immunophenotyping analysis, in accordance with the WHO classification of 2017[25]. BM was further evaluated for abnormal translocations, FLT3, or NPM mutations through cytogenetic and molecular studies. The medical records of patients were retrieved from the cancer epidemiology and statistics department. The following data were extracted: demographic data (age and sex), clinical features (organomegaly, comorbidities, performance status), laboratory parameters (CBC, BMA, FCM, karyotyping, and molecular genetic analyses), lines of treatment, dates of initial diagnosis, induction of chemotherapy, achievement of complete remission (CR), relapse and last follow-up or death. Disease-free survival (DFS) is defined as the time from confirmed CR to relapse, the last follow-up, or death. Overall survival (OS) was determined from the date of diagnosis to the last follow-up or death due to any cause. The current study received ethical approval from the Institutional Review Board of NCI, Cairo University, under approval number (CP2501-503-076-195).

The standard care of treatment in our institute for AML patients younger than 56 years (apart from APL) remains intensive chemotherapy with 7+3 protocol (Ara-C/Idarubicin or Doxorubicin) aiming for remission induction along with prophylactic antiviral therapy (Evushield) during the coronavirus disease 2019 (COVID-19) pandemic era. Unfit or elderly patients who are ineligible for intensive chemotherapy protocol receive less aggressive treatment on palliative intent including oraletoposide or low dose Ara-C. Patients were followed up for approximately 3 years after treatment.

FLT3 ITD gene assessment

FLT3 mutations were detected using PCR-based methods via the Leukostrat FLT3 Mutation Assay2.0-ABI fluorescence detection kit following the manufacturer’s protocol (Invivoscribe). Briefly, 3 mL BM was collected in an EDTA tube and DNA was extracted using QIAamp DNA Blood Mini Kit (QIAGEN^®, Austin, Texas, United States). PCR was performed on a Biometra Trio (Analytik Jena, Jena, Germany) as follows: 95 °C for 5 minutes, followed by 35 cycles of 94°C for 30 seconds, 55°C for 30 seconds, 72°C for 60 seconds, 72°C for 60 minutes, and an indefinite 4°C hold. Fragment analysis was performed by capillary electrophoresis on 3500 genetic analyzer (Thermo Fisher, Applied Biosystems, United States).

NPM1 gene mutation detection

A total of 5 μL genomic DNA was used in the ipsogen NPM1 MutaScreen kit (Qiagen, Hilden, Germany), which can distinguish both wild type and mutant NPM1. The PCR profile on the Shanghai Hongshi Medical Technology Co., Ltd.'s SLAN^®-48P Real-Time PCR System was 50°C for 2 minutes, followed by 95°C for 10 minutes, 40 cycles of 95°C for 15 seconds, and 60°C for 90 seconds. Acquisition was conducted at 60°C. Sample preparation and analysis were conducted in accordance with the manufacturer's protocol.

SOX11 gene expression

SOX11 gene expression was analyzed using BM samples from AML patients, with control samples obtained from BM donors. Following the safety guidelines, approximately 2 mL of BM sample was aspirated into an EDTA vacutainer. Cellular RNA was extracted from BM using the QIAamp RNA blood mini kit (QIAGEN^®, Austin, Texas, United States) following the manufacturer’s protocol. Approximately 1.0 μg RNA was utilized for reverse transcription employing the Applied Biosystems™ High-Capacity cDNA Reverse Transcription Kit (Thermo Fisher Scientific, United States). The resulting cDNA was subsequently stored at -20°C until needed. Rt-PCR amplification was performed using Power Up™ SYBR™ Green Master Mix (Thermo Fisher Scientific, United States), where the final volume of the Rt-PCR mix was 20 μL. Amplification was performed by programming the thermocyclers with an initial DNA polymerase activation step at 95°C for 10 minutes. Thirty-five cycles of a two-stage PCR were used, consisting of 95°C for 15 seconds and 60°C for 1 minute. β-actin was used as the housekeeping gene as previously described[26]. A melting curve was generated to ensure primer specificity for each target gene. Data from the amplification plot were obtained and analyzed to assess relative SOX11 gene expression in AML patients compared to control samples, utilizing the comparative threshold cycle method. Fold changes in SOX11 gene expression were analyzed using the 2^-ΔΔCt method.

Statistical analysis

The PASS 11 sample size calculator with 0.05 alpha error, confidence interval of 0.95 and power of the study 0.80 was used to calculate minimum sample size required to assess SOX11 expression levels in AML patients. Data coding and analysis were performed using SPSS version 24. Quantitative data were summarized using median and ranges, while categorical data were summarized as numbers and percentages. For quantitative data, comparisons between groups were performed using the Mann-Whitney test. The Kaplan-Meier method was employed to estimate DFS and OS rates, with differences across groups compared using the log-rank test. All tests were two-sided, and statistical significance was set at P < 0.05.

RESULTS

Patients’ characteristics

Out of the 102 patients included in the study, 61 (59.8%) were male and 41 (40.2%) were female. The patients’ ages varied from 18 to 78 years, with a median age of 44 years and a mean ± SD of 42.61 ± 14.7 years. Clinical and laboratory data of the patients are presented in Table 1. Peripheral blood findings revealed that the total leukocyte count varied from 11.2 to 488.9 × 10⁹/L, with a median of 37.62 × 10⁹/L. Hemoglobin levels ranged from 5.5 to 15.5 g/dL, with a mean ± SD of 7.7 ± 2.1. Platelet counts were observed between 4 and 836 × 10⁹/L, with a median of 46.5 × 10⁹/L. Additionally, peripheral blood blasts ranged from 0 to 99%, with a median of 30%. BM findings showed that 65/102 patients (63.7%) presented with hypercellular BM, 26/102 patients (25.5%) with normocellular BM, and only 11/102 (10.8%) patients presented with hypocellular BM. BM blasts of all patients ranged from 0 to 98%, with a median of 49%. CD34 was positive in 41 (40%) patients and was negative in 61 (60%) patients. According to the FAB classification, the most common subtype was M2 (44 cases, 43.1%), followed by M4 (28 cases, 27.5%), M3 (4 cases 3.9%), M1 (16 cases, 15.7%), M5 (7 cases, 6.9%), M0 (2 cases, 2%), and M6 (1 case, 1%). Cytogenetic analysis revealed that 65 patients (64%) had a normal karyotype, while 37 (36%) exhibited cytogenetic abnormalities: 9 (8.8%) had inv16, 16 (15.7%) had t (8;21), 4(3.9%) had t (15;17),4 (3.9%) had 46xy, del7, 1 (%) had 46xy, del8, del9, and 3 (2.9%) had 47xy, +8. Molecular genetic analysis revealed that 31/102 patients (30.4%) had mutant NPM1, 71 (69.6%) patients had wild NPM1, 37/102 (36.3%) patients had mutant FLT3-ITD, and 65/102 (63.7%) patients had wild-type FLT3-ITD. Clinically, 15 (14.7%) patients presented with hepatomegaly, 18 (17.6%) patients presented with splenomegaly, and 9 (8.8%) patients had lymphadenopathy. In response to induction therapy, 33/45 (73.3%) patients achieved CR, and 12/45 (26.7%) did not achieve CR. Additionally, relapse was documented in 14 (13.7%) patients (Table 1).

Table 1 Clinical and laboratory data of the acute myeloid leukemia patients.

Parameters		Frequency
Gender, n (%)	Male	61 (59.8)
	Female	41 (40.2)
Age (years)	mean ± SD	42.61 ± 14.7
	Median (IQR)	44 (18-78)
Hb (g/dL)	mean ± SD	7.7 ± 2.1
Platelets (× 109/L)	Median (IQR)	46.5 (4-836)
TLC (× 109/L)	Median (IQR)	37.62 (11.2-488.9)
PB blast	Median (IQR)	30 (0-99)
BM blast	Median (IQR)	49 (0-98)
D14 blasts	Median (IQR)	0 (0-80)
D28 blasts	Median (IQR)	0 (0-80)
BM cellularity, n (%)	Hypocellular	11 (10.8)
	Normocellular	26 (25.5)
	Hypercellular	65 (63.7)
FAB, n (%)	AML-M0	2 (2)
	AML-M1	16 (15.7)
	AML-M2	44 (43.1)
	AML-M3	4 (3.9)
	AML-M4	28 (27.5)
	AML-M5	7 (6.9)
	AML-M6	1 (1.0)
CD34, n (%)	Negative	61 (60)
	Positive	41 (40)
Cytogenetics, n (%)	Normal	65 (64)
	Abnormal	37 (36)
Cytogenetics abnormalities, n (%)	Inv 16	9 (8.8)
	t (8;21)	16 (15.7)
	t (15;17)	4 (3.9)
	46xy, del7	4 (3.9)
	46xy, del 8, del 9	1 (1)
	46xy, +8	3 (42.9)
Molecular genetics markers, n (%)
FLT3 ITD, n (%)	Negative	65 (63.7)
	Positive	37 (36.3)
NPM, n (%)	Negative	71 (69.6)
	Positive	31 (30.4)
Response to induction therapy, n (%)	CR	33 (73.3)
	No CR	12 (26.7)
Relapse/refractory, n (%)	Negative	37 (72.5)
	Positive	14 (27.5)
Death, n (%)	Negative	31 (30.4)
	Positive	71 (69.6)
Liver, n (%)	Negative	87 (85.3)
	Positive	15 (14.7)
Spleen, n (%)	Negative	84 (82.4)
	Positive	18 (17.6)
LNs affection, n (%)	Negative	93 (91.2)
	Positive	9 (8.8)

BM: Bone marrow; CR: Complete remission; Hb: Hemoglobin; LNs: Lymph nodes; PB: Peripheral blood; TLC: Total leukocyte count.

Association between SOX11 expression and patients’ characteristics

SOX11 mRNA was expressed in 84/102 (82.4%) of AML patients, and the levels ranged from 0 to 106.15, with a median of 0.07. Increased SOX11 expression was significantly associated with the presence of a FLT3-ITD mutation [median: 0.09, range: (0-2.4) vs 0.005 (0-5.9) in those negative for FLT3-ITD, P < 0.001], the FAB-M2 subtype [median: 0.35, range: (0-105), P = 0.008], and the occurrence of cytogenetic abnormalities [median: 0.1, range: (0-2.4) vs 0.01 (0-5.9) in cases with normal cytogenetics, P = 0.011]. However, there was no statistically significant association between SOX11 levels and any of the other clinical or laboratory parameters of AML patients (Table 2).

Table 2 Association between SOX expression and clinical patient features.

Assessed parameters	Value	SOX11 expression	P value
Sex	Male	0.1 (0-81.6)	0.797
	Female	0.03 (0-106)
CD34	Negative	0.05 (0-106)	0.607
	Positive	0.105 (0-105)
FLT3 ITD	Negative	0.005 (0-5.9)	P < 0.001
	Positive	0.09 (0-2.4)
NPM	Negative	0.11 (0-105)	0.166
	Positive	0.01 (0-9.5)
Liver	Negative	0.055 (0-106)	0.928
	Positive	0.09 (0-5.8)
Spleen	Negative	0.06 (0-106)	0.599
	Positive	0.05 (0-5.86)
LNs	Negative	0.05 (0-106)	0.953
	Positive	0.21 (0-5.86)
BM celularity	Hypocellular	0.09 (0-2.1)	0.268
	Normocellular	0.03 (0-82.5)
	Hypercellular	0.11 (0-106)
FAB	AML-M1	0.02 (0-106)	0.008
	AML-M2	0.35 (0-105)
	AML-M3	0.115 (0-0.21)
	AML-M4	0.015 (0-10.9)
	AML-M5	0 (0-2.9)
Cytogenetic	Normal	0.01 (0-5.9)	0.011
	Abnormal	0.1 (0-2.4)
CR	Negative	0.055 (0-6.19)	0.806
	Positive	0.145 (0-81.57)
Relapse/refractory	Negative	0.08 (0-10.9)	0.702
	Positive	0.12 (0-81.6)
Death	Negative	0.14 (0-10.9)	0.593
	Positive	0.085 (0-81.6)
Age	SOX low expression	44 (18-70)	0.784
	SOX over expression	43 (18-78)
Hb	SOX low expression	7.2 (2-14)	0.122
	SOX over expression	7.6 (5-14)
PLT	SOX low expression	47.5 (4-836)	0.921
	SOX over expression	46 (8-420)
TLC	SOX low expression	61530 (1150-387900)	0.058
	SOX over expression	30600 (1120-488900)
PB blast	SOX low expression	31 (0-97)	0.206
	SOX over expression	30 (0-97)
BM blast	SOX low expression	50 (0-98)	0.516
	SOX over expression	50 (0-96)
D14 blasts	SOX low expression	0 (0-77)	0.243
	SOX over expression	0 (0-80)
D28 blasts	SOX low expression	0 (0-53)	0.289
	SOX over expression	0 (0-80)

TLC: Total leukocyte count; PLT: Platelet counts; AML: Acute myeloid leukemia; BM: Bone marrow; CR: Complete remission; Hb: Hemoglobin; LNs: Lymph nodes; PB: Peripheral blood.

Impact of SOX11 expression on response to induction therapy in AML patients

Induction data response was obtained from only 45 patients. Among the patients, 33/45 (73.3%) patients achieved CR, while 12/45 (26.7%) did not achieve CR. The rest of the AML patients either died during the induction or lost contact during the follow-up period. There was no significant difference in SOX11 expression among AML patients in CR compared to those with no response (P = 0.81, Table 2).

Impact of SOX11 expression on patient survival

There was no significant difference in SOX11 expression among AML patients in DFS or OS rates. The median DFS for all patients was 8.3 months (95%CI: 3.489-13.111), and the median DFS of the low SOX11 expressers was 12.57 months vs 6.4 months for the high expressers (P = 0.98). The median OS for all AML patients, the median OS was 1.27 months (95%CI: 0.418- 2.122, and the median OS of the low SOX11 expressers was 1.17 months compared to 3.2 months for the high expressers (P = 0.36, Figure 1).

Figure 1 Disease-free survival and overall survival in acute myeloid leukemia patients in relation to SOX11 gene expression. A: Disease-free survival; B: Overall survival.

DISCUSSION

The approach to AML treatment has significantly improved compared to the past decade, driven by improved detection of minimal residual disease and the identification of new prognostic mutations. Given the profound heterogeneity of AML, therapeutic decision-making remains challenging, and OS rates continue to be suboptimal. However, a better understanding of the underlying pathophysiological processes has catalyzed the development of new therapeutic agents, ushering in an era of personalized medicine[27]. The introduction of targeted agents that address specific gene mutations, including FLT3, BCL-2 inhibitors, and IDH1/2, has significantly enhanced patient outcomes[5-28]. This highlights the necessity of identifying additional pathogenic pathways involved in AML transformation and progression, which may reveal new targets for intervention[5]. AML is maintained by leukemia-initiating cells. However, the roles of most transcription factors, including SOX genes, in LIC activation and expansion remain obscure[29]. SOX11 is variably expressed in several acute and chronic B-lymphoid and solid tumors. Despite its inconsistent prognostic value across various cancer tissues, it has been beneficial in diagnosis and determining appropriate treatment strategies for patients[5,11]. In vivo clinical trials in MCL demonstrated improved OS in intensively treated patients with high SOX11 expression. Imatinib treatment inhibited tumor angiogenesis and reduced lymphoma growth in SOX11-positive xenografts[30,31]. Moreover, in vitro studies in gliomas and nasopharyngeal carcinoma revealed that SOX11 overexpression increased the sensitivity of cancer cells to chemotherapy. Additionally, the application of epigenetic agents that upregulate SOX11 inhibited cancer cell proliferation and invasion[32,33]. The results suggest that measuring SOX11 expression levels may be essential for identifying lymphoma and solid tumor patients who are more likely to benefit from intensive chemotherapeutic regimens. Currently, the investigation of SOX11 expression in AML is limited. To the best of our knowledge, only one study has examined the effect of its expression on AML prognosis, indicating a negative influence on OS and DFS[24]. Nevertheless, the results of the current study did not demonstrate this adverse prognostic effect, even with a larger sample size. Our data indicates that comorbid conditions and advanced age may contribute to the adverse effects of the COVID-19 pandemic on patients, leading to delayed diagnosis and treatment, increased mortality, or loss of follow-up. NPM and FLT-ITD mutations are prevalent and related to prognosis in AML patients. In the current study, 30.4% of our patients had mutant NPM, consistent with previous reports[34,35], whereas 36.3% of the patients showed mutant FLT3-ITD similar to some studies[36,37] but higher than other studies[3,34,38], which may be attributed to different sample sizes, cohort characteristics, or different mutation assay techniques. In the current study, we found that elevated SOX11 expression was associated with the presence of the FLT-ITD mutation, consistent with the findings of Tosic et al[24]. Previous reports indicate that the upregulation of the SOX4 gene, which is structurally similar to SOX11, is associated with C/EBPα and FLT3/ITD mutations in AML[39]. Furthermore, FLT3/ITD interacts with C/EBPα and RUNX1 in the leukemogenic process[40,41]. Therefore, Tosic et al[24] proposed that these factors act synergistically with transcription factors from the SOX family. FLT-ITD mutations are primarily linked to the M2 FAB subtype and cytogenetically normal AML[36]. Interestingly, we found that higher SOX11 expression was significantly correlated with the M2 FAB subtype. Conversely, we did not detect a significant association with NPM mutations, contradicting the findings of Tosic et al[24]. However, interpretation of the prognostic significance of NPM must consider the presence of the associated FLT-ITD mutation, as recommended by the 2022 ELN risk stratification of AML[42]. The prognostic significance of NPM is limited to cases lacking the FLT-ITD mutation, whereas the role of the FLT-ITD mutation is emphasized regardless of the allelic ratio or the presence of NPM mutation. In the present study, 64% of patients presented with normal karyotype, while 36% showed cytogenetic abnormalities. The most prevalent cytogenetic aberrations were t (8;21) (15.7%), inv16 (8.8%), and t (15;17) (3.9%), consistent with the findings of Nabil et al[3]. Our findings indicate a significant correlation between cytogenetic abnormalities and increased SOX11 expression. In de novo AML, these aberrations significantly contribute to the initiation of leukemogenesis and correlate with clinical characteristics and treatment outcomes in most cases. Chromosomal instability and translocation occur during relapse in initially cytogenetically normal AML patients, identified as significant factors contributing to therapy resistance and predicting relapse[43,44]. Similarly, SOX11 is correlated with deletion 11q/17p and poor prognosis in CLL patients and was proposed as a biomarker of unstable CLL[20]. Upregulation of SOX11 has been correlated with various rearrangements in B-ALL, including ETV6-RUNX1, with improved outcome[8]. Whether SOX11 upregulation results from chromosomal changes affecting its upstream regulators or whether it contributes to the generation of chromosomal aberrations remains undefined. However, a recent systematic analysis by Sun et al[45] reported that SOX11 was positively enriched in AML in several gene regulatory mechanisms including chromosome segregation regulation, while it was negatively enriched in the regulation of cell cycle G1/S transition. SOX11 has also been reported to affect genes involved in mitosis, cell survival, and inhibition of apoptosis-related pathways[45,46]. In addition, Larson et al[47] found higher SOX11 expression in BM mesenchymal stem cell (MSCs) progenitors that progressively decreased during cell maturation. Upregulated SOX11 has been also linked to more immature or stem-like phenotypes, which are often associated with chromosomal instability[45,48]. Taken together, upregulated SOX11 may support stemness and dysregulate genes involved in cell cycle checkpoints, chromosome segregation and DNA repair mechanisms, predisposing cells to progress through the cell cycle with chromosomal instability that could result in chromosomal alterations in the form of aneuploidies, deletions or translocations. Instead, SOX11 overexpression might represent part of a leukemogenic process initiated by chromosomal translocations. A previous study by Fernando et al[49] demonstrated upregulation and a direct correlation between SOX4 and long non-coding RNA (lncRNA) CASC15 expression in AML with RUNX1 and MLL translocations. The authors suggested that these translocations result in upregulation of lncRNA CASC15, which in turn regulates the expression of the chromosomally neighboring gene SOX4. Furthermore, observations from earlier studies indicated that other SOXC members (SOX4 and SOX12) were oncogenic in AML through augmentation of the β-Catenin/Wnt signaling pathway. β-Catenin was upregulated in AML, and in MLL (KMT2A) AML, β-Catenin was critical for leukemic stem cells driven by the MLL gene[5,29]. Furthermore, Wnt signaling has been shown to upregulate SOX4 expression[11]. It is unclear whether SOX11 plays a similar role in AML, though in some cancers and in tissue remodeling, SOX11 has been suggested to collaborate with other SOXC members and several signaling pathways, including the Wnt pathway[9,46,48]. Conversely, SOX11 has been described to suppress the Wnt signaling pathway in MCL, interfering with the establishment of the β-catenin/T-cell factor complex[30]. Therefore, the interactions between SOX11 and constituents of the Wnt pathway in AML subsets require further experimental validation[11]. Consistent with the findings of Tosic et al[24], we did not identify any significant association with any other clinical or laboratory parameters. Our findings are consistent with prior studies that highlight the complexity of AML genetics and indicate a possible role for SOX11 in AML prognosis. Additional research is necessary to understand the pathogenetic mechanisms of the SOX11 gene across various AML subtypes. This may inform individualized management strategies for AML, either through the development of novel therapeutic targets or by inhibiting critical induction signals, thereby establishing a foundation for combination treatment[5].

CONCLUSION

In conclusion, the current study’s results indicate that elevated SOX11 expression is associated with FAB M2 classification and abnormal cytogenetics in patients with AML. The correlation between elevated SOX11 expression and FLT-ITD mutation may serve as a marker for identifying high-risk AML patients who could benefit from targeted or more intensive therapies. The correlation between elevated SOX11 expression and cytogenetic abnormalities may have implications for predicting the risk of translocation development and relapse in patients receiving high-risk therapy.

ACKNOWLEDGEMENTS

We thank all of the patients who participated in the study.