title: The survival and differentiation of pro-B and pre-B cells in the bone marrow is dependent on IL-7Rα Tyr449.
abstract: IL-7 is critical for murine T and B cell development and survival and plays a significant role in lymphoblastic leukemia in both humans and mice. We evaluated the role of the IL-7Rα Tyr(449) cytoplasmic SH2-binding motif in IL-7-mediated B cell development using a knock-in mouse with a Tyr to Phe mutation (IL-7Rα(449F/449F) mouse). IL-7Rα(449F/449F) and IL-7Rα(-/-) mice showed no defect in the number of pre-pro-B cells, although IL-7Rα(449F/449F) mice had decreased Ebf1 in pre-pro-B cells and impairment in B cell-committed CLPs. We identified that IL-7Rα Tyr(449) was critical for both pro-B and pre-B stages of development in the bone marrow. IL-7Rα(449F/449F) and IL-7Rα(-/-) mice had comparable precursor B cell defects, indicating that signaling from the IL-7Rα required this motif. Although the defect in IL-7Rα(449F/449F) pro-B cells was associated with loss of STAT5 activation and diminished expression of Mcl1, this was not rescued by overexpression of Bcl-2. IL-7Rα(449F/449F) and IL-7Rα(-/-) pre-B cells also showed defective cyto-Igμ and CD25 expression, associated with reduced levels of Rag1, Rag2, and Irf4. Pre-B cells from IL-7Rα(449F/449F) mice also failed to proliferate, perhaps as a result of the failure to rearrange Igμ. Our data suggest that IL-7Rα Tyr(449) was essential for IL-7Rα signaling in bone marrow B cell development and survival.
authors.affiliation: Infection, Inflammation and Immunity Research Group, Department of Microbiology and Immunology, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada; and.
authors.forename: Daniel T
authors.initials: DT
authors.lastname: Patton
authors.affiliation: Infection, Inflammation and Immunity Research Group, Department of Microbiology and Immunology, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada; and.
authors.forename: Adam W
authors.initials: AW
authors.lastname: Plumb
authors.affiliation: Infection, Inflammation and Immunity Research Group, Department of Microbiology and Immunology, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada; and Department of Zoology, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada ninan@mail.ubc.ca.
authors.forename: Ninan
authors.identifier: http://orcid.org/0000-0002-2747-1246
authors.initials: N
authors.lastname: Abraham
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D001853:Bone Marrow / Q000276:immunology*; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D049109:Cell Proliferation; D002470:Cell Survival / Q000235:genetics / Q000276:immunology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000276:immunology; D015322:Gene Rearrangement, B-Lymphocyte / Q000235:genetics / Q000276:immunology; D018398:Homeodomain Proteins / Q000235:genetics / Q000276:immunology; D006801:Humans; D007148:Immunoglobulin mu-Chains / Q000235:genetics / Q000276:immunology; D050835:Interferon Regulatory Factors / Q000235:genetics / Q000276:immunology; D053645:Interleukin-2 Receptor alpha Subunit / Q000235:genetics / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D020125:Mutation, Missense; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000235:genetics / Q000276:immunology; D054448:Precursor Cells, B-Lymphoid / Q000166:cytology / Q000276:immunology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000276:immunology; D020395:Receptors, Interleukin-7 / Q000235:genetics / Q000276:immunology*; D050799:STAT5 Transcription Factor / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D014443:Tyrosine / Q000235:genetics / Q000276:immunology; D000099218:Interferon Regulatory Factor-4
chemical_list: D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D007148:Immunoglobulin mu-Chains; D050835:Interferon Regulatory Factors; D053645:Interleukin-2 Receptor alpha Subunit; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D020395:Receptors, Interleukin-7; D050799:STAT5 Transcription Factor; D014443:Tyrosine; D000099218:Interferon Regulatory Factor-4; C508018:Il2ra protein, mouse; C579094:Mcl1 protein, mouse; C499308:Rag2 protein, mouse; C415350:interleukin-7 receptor, alpha chain; C052617:Bcl2 protein, mouse; C064658:RAG-1 protein