c-Myb expression is critical to maintain proliferation and glucose metabolism of large pre-B cells

Abstract

AbstractThe c-Myb transcription factor is required for the differentiation of CD19+ B-lineage cells and plays significant roles from the specification of the B cell lineage to the survival of pro-B cells. c-Myb coordinates the survival of pro-B cells with the expression of genes required for transition to the large pre-B cell stage of differentiation. However, it is not known if c-Myb is important for the proliferative expansion or subsequent differentiation into small pre-B cells. Here we demonstrate that c-Myb expression is important for large pre-B cell survival, proliferation, and differentiation into small pre-B cells. Utilizing genome-wide analysis, we found that c-Myb was important for maintaining glucose uptake and utilization and exogenous expression of Glut1 and Hk1 rescued large pre-B cell recovery and survival. Furthermore, we found that c-Myb is important for repression of Ikaros and Aiolos and our c-Myb-dependent gene signature was enriched in an Ikaros footprint of genes that drive cell cycle exit and the large to small pre-B cell transition. However, upon loss of c-Myb expression, inhibition of Ikaros activity was able to restore certain Ikaros-mediated gene expression changes but was insufficient to rescue recovery of large pre-B cell numbers. We found that c-Myb regulates glucose utilization and glucose-dependent survival through Hk1 in an Ikaros-independent manner. Thus, c-Myb regulation of glucose metabolism is critical to maintain large pre-B cell survival while repression of the Ikaros-mediated gene expression program is critical to prevent premature cell cycle exit and premature differentiation into small pre-B cells.