Developmental stage-specific effects of Pim-1 dysregulation on murine bone marrow B cell development.
The 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).



In 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.



These 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.
The Key Laboratory Pathobiology, Ministry of Education, Norman Bethune College of Medicine, Jilin University, Changchun, 130000, People's Republic of China.|Department of Immunology, College of Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA.
Zhihui
Z
Xu
Department of Immunology, College of Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA.
Kimberly A
KA
Gwin
The Key Laboratory Pathobiology, Ministry of Education, Norman Bethune College of Medicine, Jilin University, Changchun, 130000, People's Republic of China. ylli@mail.jlu.edu.cn.|Department of Pathology, Norman Bethune College of Medicine, Jilin University, Changchun, 130000, People's Republic of China. ylli@mail.jlu.edu.cn.
Yulin
Y
Li
Department of Immunology, College of Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA. medina.kay@mayo.edu.
Kay L
KL
Medina
D000818:Animals; D001402:B-Lymphocytes / Q000502:physiology*; D001854:Bone Marrow Cells / Q000502:physiology*; D002454:Cell Differentiation; D019070:Cell Lineage; D049109:Cell Proliferation; D002470:Cell Survival; D002478:Cells, Cultured; D006410:Hematopoiesis / Q000235:genetics; D018398:Homeodomain Proteins / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D054448:Precursor Cells, B-Lymphoid / Q000502:physiology*; D051573:Proto-Oncogene Proteins c-pim-1 / Q000235:genetics / Q000378:metabolism*; D019076:Transgenes / Q000235:genetics; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics
D018398:Homeodomain Proteins; C097899:homeobox protein HOXA9; C497971:Flt3 protein, mouse; D051941:fms-Like Tyrosine Kinase 3; C496636:Pim1 protein, mouse; D051573:Proto-Oncogene Proteins c-pim-1
B cell development; B cell precursors; Eμ-Pim1 transgene; Flt3; Hematopoiesis; Hoxa9; Lymphopoiesis; pim1-/-