Bone marrow microenvironment: The guardian of leukemia stem cells

Abstract

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.

Chronic Myeloid Leukemia Prognosis and Therapy: Criticisms and Perspectives

“…Philadelphia-positive (Ph+) chronic myeloid leukemia (CML) is a clonal myeloproliferative disease marked by chromosome translocation t(9;22) (q22;q11) that leads to the BCR-ABL1 fusion gene. The resulting BCR-ABL1 fusion protein (p210), is a constitutively activated tyrosine kinase that drives the leukemic transformation of hematopoietic stem cells, and induces the progression of the disease from the early chronic phase (CP) to the blastic phase (BP) which fatally close the course of the disease [ 1 , 2 , 3 , 4 ].…”

Ex-vivo drug testing predicts chemosensitivity in acute myeloid leukemia

“…This might be partially explained by differences in sample testing. Here, we tested whole BM which is more similar to in vivo conditions, 12 than extracting AML blasts, and has been shown to increase chemoresistance, 25‐27 and as a result it may affect ex vivo sensitivity but less so ex vivo resistance. Based on our study, PharmaFlow shows greater clinical utility in predicting clinically sensitive patients rather than resistant.…”

Nanocarriers as Magic Bullets in the Treatment of Leukemia

“…Although most of the conventional drugs and designed nanoparticles are dependent on the elimination of the bulk disease population, a small and rare population called leukemic stem cells (LSC) may be able to resist the therapy and may relapse after a while [127,128]. These leukemic stem cells, after facing ineffective therapies, evolve and change their characteristics and make a new population of LSC [129].…”

“…The population of LSC in AML is heterogeneous, and the expression of CD markers such as CD44, CD47, CD93, CD96, CD123, CLL-1, TIM-3, etc., is variable from patient to patient. Moreover, some of these markers, such as CD44 and CD47, are also expressed on normal stem/progenitor cells, thus finding specific markers of AML LSC using various techniques such as flow cytometry and cell surface capturing technology for targeted therapy by nanoparticle seems practical [127,130].…”