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c-Myb Is Required for Pro-B Cell Differentiation¹

Shawn P. Fahl,^* Rowena B. Crittenden,^* David Allman, and Timothy P. Bender^2*

^*Department of Microbiology, University of Virginia Health System, Charlottesville, VA 22908; and Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104

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 Myb^f/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 -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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Grant AI059294 from the National Institutes of Health (to T.P.B.).

² Address correspondence and reprint requests to Dr. Timothy P. Bender, Department of Microbiology, University of Virginia Health System, 1300 Jefferson Park Avenue, P.O. Box 800734, Charlottesville, VA 229080-0734. E-mail address: tpb3e{at}virginia.edu

³ Abbreviations used in this paper: HSC, hematopoietic stem cell; MPP, multipotent progenitor; LMPP, lymphoid-primed multipotent progenitor; CLP, common lymphoid progenitor; tNGFR, truncated nerve growth factor receptor; DAPI, 4',6-diamidino-2-phenylindole; PI, propidium iodide; SP, single positive; SCF, stem cell factor; miRNA, microRNA.

⁴ The online version of this article contains supplemental material.