It is clear that the c-myb protooncogene plays a crucial role during hematopoiesis. In each hematopoietic lineage, c-myb is abundantly expressed at the immature stages of differentiation and is turned off at a relatively late time during the differentiation process. However, virtually nothing is known about what role c-myb plays during hematopoietic maturation, how that role is mediated or what the signaling pathways are that regulate c-myb expression. Mice that are homozygous null at the c-myb locus die at day fifteen during embryo genesis from a severe anemia. This finding graphically demonstrated the significance of c-myb during hematopoiesis but has precluded study of c-myb activity at the later stages of differentiation. The lack of a tractable genetic system that will allow mutation of c-myb during the later stages of hematopoietic maturation has been a major impediment to understanding the role of c-myb during hematopoiesis. During B cell development in the bone marrow, c-myb is expressed in pre-B and pre-B cells but is expressed at levels approximately 20-fold lower in immature, recirculating B cells and peripheral B cells. To begin to understand the role played by c-myb during B cell development we have produced mice that carry a c-myb allele targeted with IoxP sites for deletion by the Cre recombinase. By breeding these mice to available mouse strains that direct Cre expression either to the early stages of B cell development in the bone marrow or in an inducible fashion, we will define the role played by c-myb during B cell development and the maintenance of peripheral B cell subsets. In addition, these mice will be crucial to the field and will allow one to begin to gain insight into c-myb function during hematopoiesis as well as in other systems where c-myb function remains poorly understood. The goals of this proposal are: 1) to determine at what stage c-myb expression is essential for B cell development and function, 2) to determine the consequences of inappropriate c-myb expression to B cell development and function and 3) to identify c-myb functional domains required to drive B cell development in the bone marrow.
| Fahl, Shawn P; Daamen, Andrea R; Crittenden, Rowena B et al. (2018) c-Myb Coordinates Survival and the Expression of Genes That Are Critical for the Pre-BCR Checkpoint. J Immunol 200:3450-3463 |
| Waldron, T; De Dominici, M; Soliera, A R et al. (2012) c-Myb and its target Bmi1 are required for p190BCR/ABL leukemogenesis in mouse and human cells. Leukemia 26:644-53 |
| Fahl, Shawn P; Crittenden, Rowena B; Allman, David et al. (2009) c-Myb is required for pro-B cell differentiation. J Immunol 183:5582-92 |
| Giles, Amber J; Bender, Timothy P; Ravichandran, Kodi S (2009) The adaptor protein Shc plays a key role during early B cell development. J Immunol 183:5468-76 |
| Lidonnici, Maria Rosa; Corradini, Francesca; Waldron, Todd et al. (2008) Requirement of c-Myb for p210(BCR/ABL)-dependent transformation of hematopoietic progenitors and leukemogenesis. Blood 111:4771-9 |
| Xiao, Changchun; Calado, Dinis Pedro; Galler, Gunther et al. (2007) MiR-150 controls B cell differentiation by targeting the transcription factor c-Myb. Cell 131:146-59 |
| Thomas, Matthew D; Kremer, Christopher S; Ravichandran, Kodi S et al. (2005) c-Myb is critical for B cell development and maintenance of follicular B cells. Immunity 23:275-86 |
