c-Myb Mediates Survival, Proliferation and Differentiation During B Lymphocyte Development

The c-Myb transcription factor is required for normal adult hematopoiesis, yet little is known regarding the role of c-Myb during lineage-specific differentiation due to the embryonic lethality of the Myb null mutation. Previous reports using conditional deletion of c-Myb during the pro-B cell stage of B cell development demonstrated a crucial role for c-Myb during the pre-BCR checkpoint. We have now used conditional deletion of c-Myb prior to B-lineage commitment to demonstrate that c-Myb is absolutely required for B lymphopoiesis, as there is a complete loss of peripheral B cells in these mice due to a block at the pre-pro-B to pro-B cell transition. We subsequently demonstrate that c-Myb regulates the intrinsic survival of pro-B cells by repressing expression of the pro-apoptotic proteins Bmf and Bim. The IL-7 signaling cascade also transcriptionally represses Bmf and Bim expression and c-Myb regulates expression of IL-7Rand SOCS3, two key components of the IL-7 signaling pathway. In addition, we find that c-Myb regulates differentiation to the pro-B cell stage, in part by regulating expression of the transcription factor Ebf1. Despite rescuing survival during the pro-B cell stage, overexpression of Bcl-2 does not rescue the defect across the pre-BCR checkpoint in the absence of c-Myb. We further demonstrate that c-Myb-deficient large pre-B cells are unable to proliferate in response to IL-7 or the pre-BCR. In addition to IL-7R, expression of the surrogate light chain 5 and cell cycle regulator cyclin D3, both of which are required for proliferation during the large pre-B cell stage, is decreased in the absence of c-Myb. Furthermore, expression of the chemokine receptor CXCR4,    which is required for the retention and migration of B-lineage progenitors within the bone marrow microenvironment, is decreased in the absence of c-Myb, suggesting that c-Myb may play a role in positioning B-lineage progenitors in the bone marrow. In summary, the work described in this thesis clearly demonstrates that c-Myb regulates the expression of genes that control the key signaling pathways that drive the pro-B to pre-B cell transition during B lymphopoiesis.

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