Cancer cells expand and metastasize as a result of their intrinsic genetic and epigenetic alterations and complex interactions within the normal tissue and tumor microenvironmental niches. Leukemias arise within the marrow, which is organized into specialized niches that regulate normal hematopoietic progenitor cell (HPC) homing, lodgment, maintenance, proliferation, and differentiation. Acute lymphoblastic and myeloid leukemias (ALL and AML) commonly present with significant peripheral blood cytopenias and hematosuppression that is often not attributable to marrow overcrowding. A better understanding of the cellular and molecular cross-talk between leukemic blast cells, normal HPCs, and their microenvironment might identify pathogenic mechanisms that could be targeted to suppress the malignant clone and/or block deleterious effects on normal tissues.
To characterize cellular and extrinsic interactions in leukemia-associated marrow niches, Colmone, et al., from Dorothy Sipkins’ lab at the University of Chicago, performed live-animal tracking studies in severe combined immunodeficient (SCID) mice engrafted with fluorescently labeled normal human CD34+ HPCs and a human pre-B ALL cell line (Nalm-6). Homing and migration of xenografted cells were assessed by serial, real-time, in vivo confocal and multiphoton microscopy imaging of calvarial bone marrow. Colocalization to vascular and perivascular niches was determined by fluorescent labeling for stromal cell-derived factor-1 (SDF-1), an important HPC chemoattractant and supportive molecule. They observed that both normal CD34+ HPCs and Nalm-6 cells predominantly homed to SDF-1-rich vascular niches. However, SDF-1 expression was down-modulated over time in established leukemic infiltrates, and, notably, normal HPCs that were either freshly injected or previously co-engrafted migrated to and lodged in the SDF-1-negative leukemic niches. Aberrant relocation to leukemic niches was followed by compromised HPC maintenance and mobilization with granulocyte colony-stimulating factor (G-CSF) and AMD3100 (an antagonist of the SDF-1 receptor, CXCR4), suggesting that the leukemic microenvironment entraps and poorly preserves the CD34+ cell pool. Additional studies implicated leukemia cell-derived stem cell factor (SCF), an HPC growth factor and chemoattractant, as the major stimulator of HPC migration. Indeed, anti-SCF antibodies blocked HPC exodus from normal marrow niches and maintained their survival in mice co-engrafted with Nalm-6 tumors. Similar results were observed in another immunodeficient mouse model, the non-obese diabetic (NOD)-SCID line, when co-transplanted with normal CD34+ HPCs and primary human ALL or AML cells. Moreover, histochemical analyses identified high levels of leukemia-associated SCF expression in marrow biopsies from patients with pre-B ALL, suggesting that this mechanism is clinically relevant.
This elegant study proposes an intriguing mechanism of hematopoietic suppression associated with ALL and AML. In this model, leukemia cell-derived SCF out-competed SDF-1 to induce normal HPCs to migrate from a nurturing vascular niche into a relatively inescapable and unsupportive tumor niche. If confirmed in further patient studies, therapeutic interventions targeting this pathway may be beneficial. However, these will likely need to focus on inhibiting leukemia cell SCF production, rather than blocking SCF interactions in the microenvironment, given the importance of SCF in maintaining normal hematopoiesis. On a broader scale, it will be of interest to determine whether competing tumor microenvironments are relevant mechanistic paradigms in the hematosuppression and immunosuppression associated with non-Hodgkin lymphoma and multiple myeloma — diseases for which critical elements of the tumor niche are rapidly being elucidated.1,2
Dr. Linenberger indicated no relevant conflicts of interest.