The Bone Marrow Microenvironment in B-Cell Development and Malignancy

Abstract

B lymphopoiesis is characterized by progressive loss of multipotent potential in hematopoietic stem cells, followed by commitment to differentiate into B cells, which mediate the humoral response of the adaptive immune system. This process is tightly regulated by spatially distinct bone marrow niches where cells, including mesenchymal stem and progenitor cells, endothelial cells, osteoblasts, osteoclasts, and adipocytes, interact with B-cell progenitors to direct their proliferation and differentiation. Recently, the B-cell niche has been implicated in initiating and facilitating B-cell precursor acute lymphoblastic leukemia. Leukemic cells are also capable of remodeling the B-cell niche to promote their growth and survival and evade treatment. Here, we discuss the major cellular components of bone marrow niches for B lymphopoiesis and the role of the malignant B-cell niche in disease development, treatment resistance and relapse. Further understanding of the crosstalk between leukemic cells and bone marrow niche cells will enable development of additional therapeutic strategies that target the niches in order to hinder leukemia progression.

Keywords: B-cell acute lymphoblastic leukemia (B-ALL); B-cell development; B-cell niche; bone marrow (BM); bone marrow microenvironment (BMM); leukemia.

Figure 1

The progression of B-cell development within the bone marrow microenvironment. Cells within the bone marrow microenvironment drive B lymphopoiesis by providing lineage instructive cues to B-cell progenitor populations. These cues are integrated at distinct developmental stages as B-cell progenitors move between bone marrow niches. Abbreviations: C-X-C motif chemokine ligand 12 (CXCL12); interleukin-7 (IL-7); stem cell factor (SCF); insulin-like growth factor-1 (IGF-1); delta-like 4 (Dll4); Wnt Family Member 5A (Wnt5A); mesenchymal stem and progenitor cell (MSPC); leptin receptor (LepR); CXCL12 abundant reticular (CAR); hematopoietic stem cell (HSC); common lymphoid progenitor (CLP).

Figure 2

Alterations induced in the bone marrow microenvironment by B-cell acute lymphoblastic leukemia (B-ALL). B-ALL-associated microenvironment populations support the growth and survival of B-ALL cells and also provide chemoprotection from current frontline therapies. Pro-angiogenic factors include basic fibroblast growth factor, hepatocyte growth factor and tumor necrosis factor-α(TNF-α). Pro-inflammatory cytokines include TNF-α, interleukin-6, interleukin-8, interleukin-10, interleukin-12, interferon-γ and CC chemokine ligand 2 (CCL2). Trans-endothelial migration (TEM) promoting factors include cortactin, mDia1 and vascular endothelial growth factor (VEGF). Abbreviations: receptor activator of nuclear factor kappa-B ligand (RANKL); C-X-C motif chemokine ligand 12 (CXCL12); matrix metalloproteinase-9 (MMP-9); osteopontin (OPN); granulocyte colony-stimulating factor (G-CSF); interleukin-7 (IL-7); bone morphogenic protein (BMP4); very late antigen-4 (VLA-4); annexin II (ANX2); growth arrest-specific 6 (GAS6); vascular cell adhesion molecule-1 (VCAM-1); mesenchymal stem cell (MSC); mesenchymal stem and progenitor cell (MSPC).