c-Myb Is Required for Pro-B Cell Differentiation

Abstract

The c-Myb transcription factor is required for normal adult hematopoiesis. However, the embryonic lethality of Myb-null mutations has been an impediment to identifying roles for c-Myb during lymphocyte development. We have used tissue-specific inactivation of the Myb locus in early progenitor cells to demonstrate that c-Myb is absolutely required for the differentiation of CD19+ B-lineage cells and B cell differentiation is profoundly blocked beyond the pre-pro-B cell stage in Mybf/f Mb1-cre mice. We demonstrate that c-Myb is required for the intrinsic survival of CD19+ pro-B cells as well as the proper expression of the α-chain of the IL-7 receptor (CD127) and Ebf1. However, survival of c-Myb-deficient CD19+ pro-B cells cannot be rescued by transduction with CD127-producing retrovirus, suggesting that c-Myb controls a survival pathway independent of CD127. Furthermore, c-Myb-deficient progenitor cells inefficiently generate CD19+ B-lineage cells during stromal cell culture but this process can be partially rescued with exogenous Ebf1. Thus, c-Myb does not appear to be required for commitment to B cell differentiation but is crucial for B cell differentiation to the CD19+ pro-B cell stage as well as survival of CD19+ pro-B cells. Surprisingly, forced c-Myb expression in lymphoid-primed multipotent progenitors favors differentiation toward the myeloid lineage, suggesting that proper c-Myb expression is crucial for B-lineage development.

Dynamics of the Splenic Innate-like CD19+CD45Rlo Cell Population from Adult Mice in Homeostatic and Activated Conditions

“…BrdU decay experiments revealed that this analog persisted in 19 + 45R lo BrdU + cells for ∼1 m after cessation the injections, which indicates that following one or several rounds of division, these cells remain in G 0 phase, favoring their final differentiation. In support of this hypothesis, we observed strong cmyb and weak Notch2 transcription, genes implicated in the transcriptional profile of highly differentiated B cells (42 (44). BCR ligation with anti-IgM had no effect on 19 + 45R lo cells, despite their expression of IgM.…”

B- myb is an essential regulator of hematopoietic stem cell and myeloid progenitor cell development

“…A role for c-myb in adult hematopoiesis has been shown more recently using several conditional knockout (KO) and mutant mouse models. In adult thymocytes and B lymphocytes, disruption of c-myb blocks development at the DN3 and prepro B stages, respectively (5)(6)(7)(8). c-myb expression is also required for erythropoiesis, myelopoiesis, and the development and maintenance of HSCs (9)(10)(11)(12), underscoring the importance of this gene within the entire hematopoietic compartment.…”

Regulation of hematopoietic stem cells by their mature progeny

“…Knockout mouse studies have demonstrated an absolute requirement for Myb/p300 in hematopoiesis and a series of elegant conditional mutant studies in mice have defined key roles for Myb in progression of erythropoiesis and lymphopoiesis (17)(18)(19). In contrast, Myb/p300 appears to play a repressive role in megakaryocytopoiesis.…”