Abstract
Imatinib mesylate (Gleevec) inhibits Abl1, c-Kit, and related protein tyrosine kinases (PTKs) and serves as a therapeutic for chronic myelogenous leukemia and gastrointestinal stromal tumors. Imatinib also has efficacy against various pathogens, including pathogenic mycobacteria, where it decreases bacterial load in mice, albeit at doses below those used for treating cancer. We report that imatinib at such low doses unexpectedly induces differentiation of hematopoietic stem cells and progenitors in the bone marrow, augments myelopoiesis but not lymphopoiesis, and increases numbers of myeloid cells in blood and spleen. Whereas progenitor differentiation relies on partial inhibition of c-Kit by imatinib, lineage commitment depends upon inhibition of other PTKs. Thus, imatinib mimics “emergency hematopoiesis,” a physiological innate immune response to infection. Increasing neutrophil numbers by adoptive transfer sufficed to reduce mycobacterial load, and imatinib reduced bacterial load of Franciscella spp., which do not utilize imatinib-sensitive PTKs for pathogenesis. Thus, potentiation of the immune response by imatinib at low doses may facilitate clearance of diverse microbial pathogens.
Highlights
Signaling by protein tyrosine kinases (PTKs) mediates a variety of cellular processes including migration, morphogenesis, stress responses, and cytoskeletal reorganization [1,2]
We report that imatinib at doses that are effective in clearing Mycobacterial infections but which are 10-fold lower than those used for cancer, mimics a physiological innate response to infection in the bone marrow, called the “emergency response,” in which hematopoietic stem cells and multipotent progenitors expand and differentiate into mature myeloid cells that migrate to peripheral sites
Imatinib effects occur in part via partial inhibition of cKit, suggesting a mechanism by which c-Kit controls the earliest stages of hematopoiesis
Summary
Signaling by protein tyrosine kinases (PTKs) mediates a variety of cellular processes including migration, morphogenesis, stress responses, and cytoskeletal reorganization [1,2]. Dysregulation of PTK activity causes a variety of diseases, including cancer. One such cancer, chronic myelogenous leukemia (CML), is associated with a characteristic translocation between chromosomes 9 and 22, called the “Philadelphia chromosome (Ph),” which encodes a fusion protein composed of breakpoint cluster region (BCR) protein and the PTK Abl, called BCR-ABL [3]. Expression of BCR-ABL in hematopoietic stem cells (HSCs) results in aberrant proliferation of Ph+ stem cells and the accumulation of myeloid cells in the bone marrow and blood. Imatinib selectively kills Ph+ myeloid lineage cells in the bone marrow and periphery, whose survival depends on expression of BCR-ABL. The drug does not appear to affect survival of Ph+ hematopoietic stem cells (HSCs), nor of Phcells [9]
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