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

Fahl, Shawn Patrick, Department of Microbiology, Immunology, and Cancer Biology, University of Virginia
Bender, Timothy, Department of Microbiology, University of Virginia
Ravichandran, Kodi, Department of Microbiology, University of Virginia
Lorenz, Ulrike, Department of Microbiology, University of Virginia
Erickson, Loren, Department of Microbiology, University of Virginia
Erickson, Loren, Department of Microbiology, University of Virginia

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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PHD (Doctor of Philosophy)
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