A hostel for the hostile: the bone marrow niche in hematologic neoplasms

Abstract

Our understanding of the biology of the normal hematopoietic stem cell niche has increased steadily due to improved murine models and sophisticated imaging tools. Less well understood, but of growing interest, is the interaction between cells in the bone marrow during the initiation, maintenance and treatment of hematologic neoplasms. This review summarizes the emerging concepts of the normal and leukemic hematopoietic bone marrow niche. Furthermore, it reviews current models of how the microenvironment of the bone marrow may contribute to or be modified by leukemogenesis. Finally, it provides the rationale for a "two-pronged" approach, directly targeting cancer cells themselves while also targeting the bone microenvironment to make it inhospitable to malignant cells and, ultimately, eradicating cancer stem-like cells.

Figure 1.

The normal bone marrow (BM) niche. The BM microenvironment is composed of multiple different cell populations that co-ordinately contribute to the regulation of hematopoiesis. The region near the endosteum is highly vascular and thought to be a site where transplanted hematopoietic stem/progenitor cells (HSPC) localize whereas sinusoids in the central portion of the marrow are thought to be the location of most HSPC under homeostasis. CAR cell: CXCL12-abundant reticular cell.

Figure 2.

Bone marrow (BM) anatomy. The normal bone marrow anatomy (here using the example of the femur) is composed of different types of bone, blood vessels and red and yellow marrow. HSPC reside in the red marrow where they differentiate into red blood cells, white blood cells and platelets via different progenitor stages (not shown). Yellow marrow represents largely adipocyte-rich regions with minimal hematopoiesis.

Figure 3.

Leukemia stem cells. Leukemia stem cells (LSC) in acute myeloid leukemia (AML; red), chronic myelogenous leukemia (CML; dark blue), B-cell acute lymphoblastic leukemia (B-ALL; green), chronic lymphocytic leukemia (CLL; pale blue), myelodysplastic syndrome (MDS; orange) and JAK2 V617F positive myeloproliferative neoplasia (MPN; yellow) interact with their bone marrow microenvironment via specific pathways. Specific details are provided in the text. SDF-1α: stromal-derived factor 1α; BMP: bone morphogenetic protein; BMPR: bone morphogenetic protein receptor; Gas6: growth-arrest-specific-gene 6; VEGF (A): vascular endothelial growth factor (A); SCF: stem cell factor; IL-8: interleukin-8; PlGF: placental growth factor; TPO: thrombopoietin; LIF: leukemia-inhibitory factor; PDGF: platelet-derived growth factor; Ang2: angiopoietin2; TGFβ: transforming growth factor β.

Figure 4.

Leukemia stem cell targeting. Depending on the disease entity certain therapies (red) may specifically target the interaction of leukemic stem cells with their bone marrow niche. As detailed in the text, some of these novel therapies have already entered clinical trials. FAK: focal adhesion kinase. Other abbreviations as in Figure 3.