Abstract
BackgroundThe serine threonine kinase Pim-1 has documented roles in hematopoietic progenitor and B cell precursor proliferation and survival. Pim-1 is a molecular target of the transcription factor Hoxa9. Previous studies showed that Pim-1 deficiency phenocopied the hematopoietic progenitor defect in hoxa9-/- mice and forced expression of Pim-1 normalized the in vitro proliferation defect inherent to hoxa9-/- hematopoietic progenitors. Pim-1 is induced by cytokine signaling, including the early lymphoid/B lineage regulators Flt3 and IL-7, and expression levels were shown to influence the size of the B cell compartment in bone marrow (BM).ResultsIn this study, we sought to determine if transgenic expression of Pim-1, driven by the immunoglobulin enhancer, Eμ, was sufficient to rescue the lymphoid/B cell precursor defect in hoxa9 or flt3-ligand (flt3l) deficient mice. Unexpectedly, expression of Eμ − Pim1 exacerbated lymphoid progenitor deficiencies in flt3l-/-, and to a lesser extent, hoxa9-/- mice. Furthermore, Eμ − Pim1 expression alone reduced early myeloid and lymphoid, but not erythroid, progenitors. In contrast, Pim-1 deficiency had no significant effect on early lymphoid/B cell development through the Pre-Pro-B cell stage, but caused a significant reduction in IgM− B cell precursors. Importantly, loss of Pim-1 did not phenocopy hoxa9- or flt3l-deficiency on the lymphoid/early B cell progenitor pools.ConclusionsThese experimental findings demonstrate that Pim-1 overexpression has developmental-stage-specific effects on B lymphopoiesis and myelopoiesis. Importantly, these suggest that Pim-1 deficiency does not contribute significantly to the early lymphoid/B cell developmental deficiency in hoxa9-/- or flt3l-/- mice.
Highlights
The serine threonine kinase Pim-1 has documented roles in hematopoietic progenitor and B cell precursor proliferation and survival
In this study we evaluated the role of Pim-1 in murine lymphoid lineage specification and B cell development through comparative flow cytometric analysis of hoxa9-/- x Eμ-Pim1Tg, flt3l-/- x Eμ-Pim1Tg, Eμ-Pim1 transgenic, pim1-/, hoxa9-/, and flt3l-/- mice
While numbers of IgM− B cell precursors (BCP) and IgM+ B cells in Eμ-Pim1 transgenic mice were comparable to WT (Fig. 3a), we found that IgM−, but not IgM+, BCPs were reduced in pim1-/- mice [10]
Summary
The serine threonine kinase Pim-1 has documented roles in hematopoietic progenitor and B cell precursor proliferation and survival. Pim-1 is induced by cytokine signaling, including the early lymphoid/B lineage regulators Flt and IL-7, and expression levels were shown to influence the size of the B cell compartment in bone marrow (BM). The steady-state production of B lineage lymphocytes in bone marrow is contingent on the developmental-stagespecific expression and combinatorial activities of multiple regulatory proteins including transcription factors, signaling molecules, microRNAs, and epigenetic modifiers. Pim1-/- Pre-B cells exhibited impaired in vitro proliferation in response to IL-7 and stem cell factor (SCF) that was rescued by expression of a functional Pim-1 transgene [10]. Overexpression of Pim-1increased numbers of IL-7 + SCF responsive B cell colonies These combined data provided the first evidence that Pim-1 was an important regulator of B lymphopoiesis in mice, and linked Pim-1 to the IL-7R signaling pathway
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