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 Tyr449 cytoplasmic SH2-binding motif in IL-7–mediated B cell development using a knock-in mouse with a Tyr to Phe mutation (IL-7Rα449F/449F mouse). IL-7Rα449F/449F and IL-7Rα−/− mice showed no defect in the number of pre–pro-B cells, although IL-7Rα449F/449F mice had decreased Ebf1 in pre–pro-B cells and impairment in B cell–committed CLPs. We identified that IL-7Rα Tyr449 was critical for both pro-B and pre-B stages of development in the bone marrow. IL-7Rα449F/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-7Rα449F/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-7Rα449F/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-7Rα449F/449F mice also failed to proliferate, perhaps as a result of the failure to rearrange Igμ. Our data suggest that IL-7Rα Tyr449 was essential for IL-7Rα signaling in bone marrow B cell development and survival.