Copyright ©The Author(s) 2019. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Stem Cells. Aug 26, 2019; 11(8): 476-490
Published online Aug 26, 2019. doi: 10.4252/wjsc.v11.i8.476
Bone marrow microenvironment: The guardian of leukemia stem cells
Mohammad Houshmand, Teresa Mortera Blanco, Paola Circosta, Narjes Yazdi, Alireza Kazemi, Giuseppe Saglio, Mahin Nikougoftar Zarif
Mohammad Houshmand, Paola Circosta, Giuseppe Saglio, Department of Clinical and Biological Sciences, University of Turin, Turin 10126, Italy
Teresa Mortera Blanco, Mahin Nikougoftar Zarif, Center for Hematology and Regenerative Medicine, Karolinska Institutet, Department of Medicine, Karolinska University Hospital Huddinge, Stockholm 14183, Sweden
Narjes Yazdi, Department of Molecular Genetics, Tehran Medical Branch, Islamic Azad University, Tehran 1916893813, Iran
Alireza Kazemi, Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran 1985717443, Iran
Mahin Nikougoftar Zarif, Blood Transfusion Research Center, High Institute for Research and Education in Transfusion Medicine, Tehran 146651157, Iran
Author contributions: Houshmand M wrote and edited the article and prepared the figures; Circosta P, Yazdi N, and Kazemi A wrote the paper; Mortera Blanco T and Saglio G edited the manuscript for important scientific content; Nikougoftar Zarif M wrote and prepared the final edition of the article.
Conflict-of-interest statement: There is no conflict of interest for any author.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Corresponding author: Mahin Nikougoftar Zarif, PhD, Associate Professor, Blood Transfusion Research Center, High Institute for Research and Education in Transfusion Medicine, Tehran 146651157, Iran.
Telephone: +98-21-88601575 Fax: +98-21-88601576
Received: March 12, 2019
Peer-review started: March 15, 2019
First decision: June 4, 2019
Revised: June 13, 2019
Accepted: June 20, 2019
Article in press: June 20, 2019
Published online: August 26, 2019

Bone marrow microenvironment (BMM) is the main sanctuary of leukemic stem cells (LSCs) and protects these cells against conventional therapies. However, it may open up an opportunity to target LSCs by breaking the close connection between LSCs and the BMM. The elimination of LSCs is of high importance, since they follow cancer stem cell theory as a part of this population. Based on cancer stem cell theory, a cell with stem cell-like features stands at the apex of the hierarchy and produces a heterogeneous population and governs the disease. Secretion of cytokines, chemokines, and extracellular vesicles, whether through autocrine or paracrine mechanisms by activation of downstream signaling pathways in LSCs, favors their persistence and makes the BMM less hospitable for normal stem cells. While all details about the interactions of the BMM and LSCs remain to be elucidated, some clinical trials have been designed to limit these reciprocal interactions to cure leukemia more effectively. In this review, we focus on chronic myeloid leukemia and acute myeloid leukemia LSCs and their milieu in the bone marrow, how to segregate them from the normal compartment, and finally the possible ways to eliminate these cells.

Keywords: Bone marrow microenvironment, Bone marrow niche, Leukemic stem cell, Chronic myeloid leukemia, Acute myeloid leukemia, Target therapy

Core tip: Chronic myeloid leukemia stem cells (LSCs) and acute myeloid LSCs are resistant to common therapies due to the activation of downstream signaling pathways that guarantee their survival. In addition, they are smart enough to escape immune surveillance. Bone marrow microenvironment underlies these phenomena by providing an environment that favors leukemia development. Recent studies confirm that targeting LSCs and their crosstalk with the bone marrow microenvironment significantly reduced residual disease burden and eventuated in LSCs removal.