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.

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

Figure 1

Cancer stem cell theory.

Figure 2

CML LSCs and their interaction with the bone marrow microenvironment. Expression of CXCR4 is downregulated by kinase activity of P210^BCRABL1, and secretion of G-CSF and expression of CD26 by CML LSCs altogether lead to mobilization of CML LSCs into the blood. At the same time, secretion of some proteins such as bone morphogenetic protein 4, miR-126, and other chemokines and cytokines through autocrine or paracrine mechanisms may support dormancy, growth, and drug resistance of CML LSCs. CML LSC: Chronic myeloid leukemia stem cell; HSC: Hematopoietic stem cell; CAR cell: CXCL12-abundant reticular cell; G-CSF: Granulocyte-colony stimulating factor; CXCL12: C-X-C motif chemokine ligand 12; CXCR4: C-X-C chemokine receptor type 4; BMP4: Bone morphogenetic protein 4.

Figure 3

AML LSCs and their interaction with the bone marrow microenvironment in contrast to chronic myeloid leukemia stem cells, AML LSCs have high expression of CXCR4 that help them to reside in the bone marrow microenvironment. Meanwhile, autocrine secretion of IL-8 by AML LSCs increases their survival. Enhanced secretion of pro-angiogenesis factors via autocrine and paracrine mechanism extends angiogenesis, which by providing metabolites and oxygen for AML LSCs leads to leukemia progression. AML LSCs: Acute myeloid leukemia stem cell; HSC: Hematopoietic stem cell; CAR cell: CXCL12-abundant reticular cell; CXCL12: C-X-C motif chemokine ligand 12; CXCR4: C-X-C chemokine receptor type 4; CXCR2: C-X-C chemokine receptor type 2; IL-8: Interleukin-8.

Figure 4

Detection of AML and CML LSCs. While CML LSCs in chronic phase are in CD34+/CD38-, using CD26 helps to segregate them from normal hematopoietic stem cells. In AML, CD34 is not a fixed marker for detection of AML LSCs, and due to the heterogeneity of AML LSC populations, other markers are needed to identify these cells. CLL-1: C-type lectin-like molecule-1; TIM-3: T-cell immunoglobulin and mucin domain-3; AML LSCs: Acute myeloid leukemia stem cell; HSC: Hematopoietic stem cell; CML LSCs: Chronic myeloid leukemia stem cells.