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J. Biol. Chem. 278 (27): 25158-25165

© 2003 by The American Society for Biochemistry and Molecular Biology, Inc.

BCL-2 and BCL-XL Restrict Lineage Choice during Hematopoietic Differentiation*

Loralee Haughn {ddagger} §, Robert G. Hawley ¶, Deborah K. Morrison ||, Harald von Boehmer §, and David M. Hockenbery {ddagger} **

{ddagger}Divisions of Human Biology and Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, the Hematopoiesis Department, Jerome H. Holland Laboratory, American Red Cross, Rockville, Maryland 20855, the ||Cellular Growth Mechanisms Section, NCI-Frederick Cancer Research & Development Center, National Institutes of Health, Frederick, Maryland 21702, and the §Department of Cancer Immunology & AIDS, Dana-Farber Cancer Institute, Boston, Massachusetts 02115

Abstract: Differentiation of hematopoietic cells from multipotential progenitors is regulated by multiple growth factors and cytokines. A prominent feature of these soluble factors is promotion of cell survival, in part mediated by expression of either of the anti-apoptotic proteins, BCL-2 and BCL-XL. The complex expression pattern of these frequently redundant survival factors during hematopoiesis may indicate a role in lineage determination. To investigate the latter possibility, we analyzed factor-dependent cell-Patersen (FDCP)-Mix multipotent progenitor cells in which we stably expressed BCL-2 or BCL-XL. Each factor maintained complete survival of interleukin-3 (IL-3)-deprived FDCP-Mix cells but, unexpectedly, directed FDCP-Mix cells along restricted and divergent differentiation pathways. Thus, IL-3-deprived FDCP-Mix BCL-2 cells differentiated exclusively to granulocytes and monocytes/macrophages, whereas FDCP-Mix BCL-XL cells became erythroid. FDCP-Mix BCL-2 cells grown in IL-3 were distinguished from FDCP-Mix and FDCP-Mix BCL-XL cells by a striking reduction in cellular levels of Raf-1 protein. Replacement of the BCL-2 BH4 domain with the related BCL-XL BH4 sequence resulted in a switch of FDCP-Mix BCL-2 cells to erythroid fate accompanied by persistence of Raf-1 protein expression. Moreover, enforced expression of Raf-1 redirected FDCP-Mix BCL-2 cells to an erythroid fate, and prohibited generation of myeloid cells. These results identify novel roles for BCL-2 and BCL-XL in cell fate decisions beyond cell survival. These effects are associated with differential regulation of Raf-1 expression, perhaps involving the previously identified interaction between BCL-2-BH4 and the catalytic domain of Raf-1.

Received for publication December 17, 2002. Revision received April 24, 2003.

* This work was supported by National Institutes of Health Grant IP50HL54881 (to D. M. H.) and by a Cancer Research Institute fellow-ship (to L. H.). 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.

** To whom correspondence should be addressed: Divisions of Human Biology and Clinical Research, Fred Hutchinson Cancer Research Center, Mailstop D2–190, 1100 Fairview Ave. N., Seattle, WA 98109. Tel.: 206-667-4611; Fax: 206-667-6519; E-mail: dhockenb{at}

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