For most new leukemia patients, the initial clinical symptoms include some combination of fatigue, bleeding, and infection — all the result of deficits in blood cell production. The diagnostic bone marrow at presentation often shows nearcomplete replacement of hematopoietic tissue by infiltrating leukemic blasts. Intuitively, the peripheral cytopenias that reflect the loss of normal hematopoietic function are seen as a manifestation of unrestrained leukemic expansion resulting in “over-crowding” of the bone marrow by malignant cells. However, this straightforward notion of passive loss of hematopoietic tissue is called into question by the observation that cytopenias are a common feature of patients in early relapse when the bone marrow leukemia burden is low. Schepers et al. now provide evidence that the loss of hematopoietic function is an active process whereby bone marrow stromal cells are reprogrammed by invading neoplastic cells to promote both leukemic expansion and HSC suppression.
Normal Versus Leukemic Bone Marrow Niche. Figure depicting a normal bone marrow niche with functional hematopoiesis, versus a re-programmed “leukemic” niche where hematopoietic stem cells (HSCs) are lost and HSC maintenance is impaired, favoring leukemic proliferation. Impaired maintenance of hematopoiesis occurs through leukemia-driven expansion of an altered early osteoblastic lineage precursor cell population (OBC) with down-regulated HSC retention signaling factors such as stem cell factor (SCF), chemokine ligand 12 (CXCL-12), and angiopoietin (Angpt1). The altered OBC expansion follows direct leukemic influence on the parent, multipotent stromal cell (MSC) population, rather than on the OBCs themselves, possibly through alterations in chemokine ligand-3 (CCL-3), thrombopoietin (TPO), direct cell contact, or other means.Figure created by Dr. Shelton Viola.
Normal Versus Leukemic Bone Marrow Niche. Figure depicting a normal bone marrow niche with functional hematopoiesis, versus a re-programmed “leukemic” niche where hematopoietic stem cells (HSCs) are lost and HSC maintenance is impaired, favoring leukemic proliferation. Impaired maintenance of hematopoiesis occurs through leukemia-driven expansion of an altered early osteoblastic lineage precursor cell population (OBC) with down-regulated HSC retention signaling factors such as stem cell factor (SCF), chemokine ligand 12 (CXCL-12), and angiopoietin (Angpt1). The altered OBC expansion follows direct leukemic influence on the parent, multipotent stromal cell (MSC) population, rather than on the OBCs themselves, possibly through alterations in chemokine ligand-3 (CCL-3), thrombopoietin (TPO), direct cell contact, or other means.Figure created by Dr. Shelton Viola.
Like other organs, the bone marrow microenvironment functions as a unit where the complex interplay of the different cell types sustains normal organ function (hematopoiesis in the case of the bone marrow). Multipotent stromal cells (MSCs) and their osteoblastic progeny (osteoblastic lineage cells, OBCs) provide critical support for the maintenance of normal hematopoietic stem cell (HSC) homeostasis. In the current study, Koen Schepers and colleagues in the laboratory of Emmanuelle Passegué at the University of California, San Francisco, used a transgenic mouse model of chronic myeloid leukemia (CML) to investigate the effects of leukemogenesis on the function of the bone marrow niche. Experimental animals, expressing inducible BCR/ABL that drives myeloid expansion, developed a florid myeloproliferative neoplasm (MPN) within six weeks. Bone marrow analysis showed preferential expansion of the OBCs, and subsequent experiments demonstrated that the expanded population was derived from MSCs that had been induced by leukemic stem cells to overproduce OBCs. Thus, the overproduction of OBCs was orchestrated by the MPN cells. Subsequent experiments suggested that thrombopoietin, CCL3, and cell-cell interactions drove the expansion of OBCs. Examination of the bone marrow showed morphologic features (fibrosis and trabecular bone thickening) reminiscent of those observed in patients with MPNs. The process was both reversible (upon eradication of leukemic cells from the bone marrow) and transplantable (sublethally irradiated wild-type mice transplanted with leukemia cells developed MPN, OBC expansion, and BM fibrosis). Aberrant expression of TGF-b, Notch, and inflammatory signaling appeared to contribute to OBC-dependent remodeling. Notably, engraftment in recipients was significantly impaired when normal HSCs were co-cultured ex vivo with leukemia-expanded OBCs, supporting the concept that the leukemia-induced OBCs negatively affect normal HSC function. The authors investigated the molecular basis of this observation and found that leukemia-conditioned OBCs aberrantly expressed several key molecules known to coordinate niche function and HSC retention, including the chemokine CXCL12, n-cadherin, stem cell factor, angiopoietin-1, and transforming TGF-b-1 and -2. The findings of Schepers and colleagues echo the results of a recent study by Zhang et al.1 that demonstrated a similar sequence of events that also implicated CXCL12 and granulocyte colony-stimulating factor as mediators of these processes. The data indicate that leukemia cells diminish hematopoietic-supportive capacity indirectly through changes in the physical and cytokine environment mediated by leukemia-expanded OBCs. The mechanisms by which the neoplastic cells sustain this microenvironment that favors leukemogenesis at the expense of normal hematopoiesis remain enigmatic.
In Brief
The study by Schepers and colleagues describes an active process in which reprogramming of niche components by neoplastic cells favors leukemic proliferation while compromising normal hematopoiesis. Microenvironmental contributions to leukemic drug resistance have long been appreciated, and the current work suggests that, similarly, leukemia-associated bone marrow dysfunction is an elegantly orchestrated component of the leukemic process rather than a simple case of physical competition for available space and resources within the bone marrow. The systematic dissection of events that convert the bone marrow from a nurturing environment to a hostile niche may hold important translational value for the treatment of hematopoietic neoplasms.
