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. 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. Hematopoietic cells are derived from multipotent progenitors present in small numbers in the adult bone marrow. Asym-metric cell divisions generate daughter cells committed to differentiation, and subsequent cell divisions are accompanied by progressive restrictions on multilineage potential. Lineage commitment appears stochastic in single cell assays of primitive hematopoietic precursors grown in multiple growth factors (1Ogawa M. Int. J. Hematol. 1999; 69: 2-5Google Scholar). Certain growth factors act to increase commitment and/or expansion of specific lineages, suggesting that lineage choice is also subject to instructive signals from the microenvironment (2Domen J. Weissman I.L. Mol. Med. Today. 1999; 5: 201-208Google Scholar, 3Metcalf D. Semin. Hematol. 1999; 36: 5-12Google Scholar). Owing to redundancies in signal transduction pathways from lineage-selective growth factor receptors, the processes leading to alternative lineage fates remain largely unknown. Growth factors, which also maintain cell survival, in addition provide general anti-apoptotic signals through receptors expressed on specific cell types. Members of the BCL-2 family of apoptotic regulators have strong effects on cell survival (4Adams J.M. Huang D.C. Puthalakath H. Bouillet P. Vairo G. Moriishi K. Hausmann G. O'Reilly L. Newton K. Ogilvy S. Bath M.L. Print C.G. Harris A.W. Strasser A. Cory S. Cold Spring Harbor Symp. Quant. Biol. 1999; 64: 351-358Google Scholar, 5Chao D.T. Korsmeyer S.J. Annu. Rev. Immunol. 1998; 16: 395-419Google Scholar, 6Reed J.C. Nature. 1997; 387: 773-776Google Scholar). However, there is mounting evidence that non-lethal cell pathways are also affected by these proteins (7Pietenpol J.A. Papadopoulos N. Markowitz S. Willson J.K. Kinzler K.W. Vogelstein B. Cancer Res. 1994; 54: 3714-3717Google Scholar). For instance, BCL-2 and BCL-XL delay cell cycle re-entry. These effects can be separated from anti-apoptotic activities by mutations in the BH4 domain and, in one example, appear to involve binding of the cytoplasmic serine-threonine phosphatase, calcineurin, to the BH4 domain of BCL-2 (8Huang D.C.S. O'Reilly L.A. Strasser A. Cory S. EMBO J. 1997; 16: 4628-4638Google Scholar, 9Shibasaki F. Kondo E. Akagi T. McKeon F. Nature. 1997; 386: 728-731Google Scholar). This agrees with earlier reports demonstrating a block to nuclear translocation of nuclear factor of activated T cells (NFAT) with overexpression of BCL-2 in T lymphocytes (10Linette G.P. Li Y. Roth K. Korsmeyer S.J. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 9545-9552Google Scholar). BCL-2 expression influences differentiation in several cell types, including hematopoietic, neuronal, and epithelial cells (4Adams J.M. Huang D.C. Puthalakath H. Bouillet P. Vairo G. Moriishi K. Hausmann G. O'Reilly L. Newton K. Ogilvy S. Bath M.L. Print C.G. Harris A.W. Strasser A. Cory S. Cold Spring Harbor Symp. Quant. Biol. 1999; 64: 351-358Google Scholar). Mice deficient for interleukin-7 or its receptor have a block in T lymphocyte development, which can be partially restored by introduction of a BCL2 transgene (11Akashi K. Kondo M. von Freeden-Jeffry U. Murray R. Weissman I.L. Cell. 1997; 89: 1033-1041Google Scholar, 12Maraskovsky E. O'Reilly L.A. Teepe M. Corcoran L.M. Peschon J.J. Strasser A. Cell. 1997; 89: 1011-1019Google Scholar). BCL-2 rescues macrophage development in macrophage-colony stimulating factor-deficient, osteopetrotic mice (13Lagasse E. Weissman I.L. Cell. 1997; 89: 1021-1031Google Scholar). In addition, BCL-2 promotes regeneration and growth of severed axons in retinal ganglion cells from adult mice and accelerates neuronal differentiation in PC-12 cells (14Sato N. Hotta K. Waguri S. Nitatori T. Tohyama K. Tsujimoto Y. Uchiyama Y. J. Neurobiol. 1994; 25: 1227-1234Google Scholar, 15Chen D.F. Schneider G.E. Martinou J.C. Tonegawa S. Nature. 1997; 385: 434-439Google Scholar). In contrast, keratinocyte differentiation and expression of the squamous cell differentiation markers, keratin 10/11 and involucrin, are inhibited by BCL-2 (16Harada H. Mitsuyasu T. Seta Y. Maruoka Y. Toyoshima K. Yasumoto S. J. Oral Pathol. Med. 1998; 27: 11-17Google Scholar). The effects of BCL-2 on retinal ganglion cells and keratinocytes are not attributable to the rescue of dying cells and are not reproduced by anti-apoptotic caspase inhibitors. Adding another level of complexity, BCL-2 and BCL-XL may have specific, non-homologous functions in hematopoiesis (4Adams J.M. Huang D.C. Puthalakath H. Bouillet P. Vairo G. Moriishi K. Hausmann G. O'Reilly L. Newton K. Ogilvy S. Bath M.L. Print C.G. Harris A.W. Strasser A. Cory S. Cold Spring Harbor Symp. Quant. Biol. 1999; 64: 351-358Google Scholar). BCL-2 and BCL-XL have reciprocal expression patterns in developing T and B lymphocytes and primitive human and murine hematopoietic precursor cells (17Josefsen D. Myklebust J.H. Lomo J. Sioud M. Blomhoff H.K. Smeland E.B. Stem Cells. 2000; 18: 261-272Google Scholar, 18Park J.R. Bernstein I.D. Hockenbery D.M. Blood. 1995; 86: 868-876Google Scholar). In this report, we utilize either BCL-2 or BCL-XL to maintain survival of FDCPMix 1The abbreviations used are: FDCP-Mix, factor-dependent cell-Patersen; IL-3, interleukin-3; GFP, green fluorescent protein; IRES, internal ribosomal entry site; ZVAD-fmk, zVal-Ala-Asp-CH2F; BH1–4, BCL-2 homology domains 1–4; GA, geldanamycin. progenitor cells during growth factor withdrawal. We demonstrate that both BCL-2 and BCL-XL enable hematopoietic differentiation in the absence of additional growth factors, but each acts along divergent and restricted pathways. Over-expression of BCL-2 supports the development of myeloid lineages and is linked to striking changes in the expression of Raf-1 kinase. In contrast, BCL-XL restricts FDCP-Mix cells to an erythroid fate. Our results provide a basis for lineage restriction in FDCP-Mix cells and demonstrate that BCL-2 and BCL-XL are unexpected participants in this process. Specific interactions with cytoplasmic signaling pathways may govern multiple cell fate decisions for BCL-2-related proteins with otherwise redundant survival functions. Cell Lines and Expression of cDNAs—FDCP-Mix (clone A4) cells were grown in Iscove's modified Dulbecco's medium (Invitrogen), containing 20% horse serum (Invitrogen), and 4% rIL-3-containing supernatant (19Karasuyama H. Melchers F. Eur. J. Immunol. 1988; 18: 97-104Google Scholar). Cells were infected with retrovirus (MIZV: MSCV 5′ LTRX-IRES-zeocin vector) encoding wild type or mutant human Raf-1, human BCL-2, human BCL-XL, or BCL-2 BH4Bcl-x, and selected in 0.6–0.8 mg/ml zeocin (Cayla, France) (20Hawley R.G. Lieu F.H.L. Fong A.Z.C. Goldman S.J. Leonard J.P. Hawley T.S. Ann. N. Y. Acad. Sci. 1996; 795: 341-345Google Scholar). Alternatively, FDCP-Mix cells were stably transfected with SFFV-Bcl2 or SFFV-BclxL plasmids by electroporation (260 volts, 960 microfarads), and selected in 0.75 mg/ml active Geneticin (Invitrogen) (21Haughn L. Leung B. Boise L. Veillette A. Thompson C. Julius M. J. Exp. Med. 1998; 188: 1575-1586Google Scholar). Cells were cloned by micro-manipulation into 96-well flat-bottomed plates with 5 × 105 irradiated C57BL/6 spleen cells/well and 4% rIL-3 supernatant. For serial expression of two genes, FDCP-Mix cells were initially transduced with c-Raf1 retroviral vectors and subsequently transfected with BCL2 or BCLXL plasmids. Retroviral supernatants were generated by calcium phosphate transfection of 293T cells, along with helper plasmids. Supernatants were collected over 4 days, pooled and concentrated by ultracentrifugation. FDCP-Mix cells were spin-infected with supernatants at a multiplicity of infection of 10:1 in the presence of 4 μg/ml Polybrene. Differentiation Assays—Cells were starved for IL-3 by washing once in phosphate-buffered saline with 5% horse serum and seeding at 3 × 104 cells/well in 24-well plates with Iscove's modified Dulbecco's medium containing 20% horse serum. Cytospins were performed after 40 h and stained with May-Grunwald-Giemsa (Sigma). For flow cytometry analysis of Gr-1 expression, cells were preincubated with 24G2 supernatant (Fc-block), and stained with biotinylated-anti-Gr-1 or IgG2b isotype controls. Cells were subsequently stained with streptavidinallophycocyanin (BD Pharmingen). 100,000 cells were analyzed per sample on a FACSCalibur®; data were analyzed using Cell Quest software (BD Biosciences). Antibodies—Antibodies to Raf-1 (R19120), Hsp90, BCL-2, and BCL-XL were obtained from Transduction Laboratories. Antibodies to Raf-1 (URP26K), Gr-1, and biotinylated isotype controls were obtained from BD Pharmingen. Anti-FLAG (M2) obtained from obtained from and from BD Pharmingen. from were with either for or IL-3 of the cell were and for nuclear cells were in and to for on Each to with a and by were at for 5 in a and were in for on by for 5 at sample containing to each for 5 a for and for of separated on and to by for c-Raf1 by of and by were by with and on Biosciences). mutant by Huang and for mutant or wild type BCLXL were by and into the retroviral The retroviral for expression of and green fluorescent protein derived from the by the into which an cloned C. H. J. Exp. Med. 2000; Scholar). BCL2 or BCLXL were cloned into were by obtained from obtained from BCL-2 and on Cell progenitor cells were infected with retroviral vectors containing human BCL2 or BCLXL were derived from single cells to 96-well plates by with expression of human BCL-2 or BCL-XL protein by were selected for FDCP-Mix cells, and FDCP-Mix FDCPMix BCL-2, and FDCP-Mix BCL-XL growth and maintained in the presence of IL-3 and IL-3 from FDCP-Mix BCL-2 or FDCP-Mix BCL-XL cell but for at In contrast, both FDCP-Mix and FDCP-Mix cells IL-3 of cells were at Cytospins of FDCP-Mix BCL-2 were performed after 40 h of IL-3 and by May-Grunwald-Giemsa A complete in to and The of granulocytes to FDCP-Mix BCL-2 from to In FDCP-Mix BCL-2 of cells with erythroid were FDCP-Mix BCL-XL were In striking to the results for BCL-2, cells to IL-3 with granulocytes or This also in a of 40 of each FDCP-Mix BCL-2 and FDCP-Mix BCL-XL the pattern of restricted myeloid and erythroid differentiation, IL-3 and A small of were in each of the two of transduced FDCP-Mix These also restricted differentiation but with the pattern to the of Thus, FDCPMix BCL-2 and FDCP-Mix BCL-XL restricted erythroid and myeloid after IL-3 and expression levels of human BCL-2 in the not with specific lineage fate To the that the restricted differentiation we were a of the we generated BCL2 and retroviral vectors containing an internal ribosomal entry of the FDCP-Mix cells were for expression by flow cytometry at h after transduction We that the cells in rIL-3 medium the of cells, that of cells at 40 cells were in IL-3 and for differentiation after 40 FDCP-Mix cells a primitive cell these Cells transduced with the differentiated into myeloid lineage cells in in contrast, IL-3-deprived cells exclusively and To the restricted differentiation in the FDCP-Mix BCL-2 and FDCP-Mix BCL-XL we analyzed for FDCP-Mix BCL-2 the Gr-1, IL-3 whereas FDCPMix BCL-XL cells by flow cytometry differentiation by expression of the by and by of in IL-3-deprived FDCP-Mix BCL-XL but not FDCP-Mix BCL-2 not FDCP-Mix BCL-XL levels of in the absence of IL-3, with to expressed in FDCP-Mix BCL-2 FDCP-Mix BCL-XL, but not FDCP-Mix BCL-2 expressed the factor These results the of restricted myeloid and erythroid Thus, BCL-2 expression myeloid lineage and BCL-XL expression erythroid cell fate, in which cell survival appears to Raf-1 Expression in FDCP-Mix IL-3 Differentiation of addition to with family BCL-2 with several cytoplasmic proteins, including calcineurin, Raf-1 and J.C. Nature. 1997; 387: 773-776Google Scholar). In a of these proteins, we in Raf-1 expression between FDCP-Mix BCL-2 and FDCP-Mix BCL-XL Raf-1 protein by of cell from FDCP-Mix BCL-2 that myeloid cells FDCP-Mix the of Raf-1 expression in FDCPMix grown in of IL-3 and In contrast, Raf-1 protein in FDCP-Mix at levels to and FDCP-Mix controls A and We obtained an with two The BCL-2 and BCL-XL with differentiation We to Raf-1 in the single FDCP-Mix but each of the FDCP-Mix expressed Raf-1 protein A and Thus, presence or absence of Raf-1 protein in IL-3 with complete the differentiation for that IL-3 withdrawal. The of Raf-1 expression on cell differentiation over the effects of BCL-2 and BCL-XL, suggesting that Raf-1 acts of BCL-2 and BCL-XL. However, in Raf-1 expression are to the anti-apoptotic functions of BCL-2 and BCL-XL, survival of both of FDCP-Mix BCL-2 and FDCP-Mix BCL-XL at 40 The family of two additional and is expressed in whereas Raf-1 and are expressed 5: Scholar). We expression by The protein expressed at levels in IL-3 of FDCP-Mix BCL-2, FDCP-Mix BCL-XL, and FDCP-Mix cells, with in IL-3-deprived cells Thus, the of Raf-1 expression in FDCP-Mix cells not a general of protein expression but appears to be specific for Raf-1, related family of cytoplasmic expression of in FDCP-Mix BCL-2, FDCP-Mix BCL-XL, and FDCP-Mix cells Moreover, levels were in FDCP-Mix and FDCP-Mix and, of specific differentiation These results indicate a for the in Raf-1 protein in the presence of Raf-1 the BCL-2 BH4 The BCL-2 homology 4 domains are of each The BCL-2 and BCL-XL BH4 in the of and the BCL-2-BH4 domain to with Raf-1, and calcineurin, interactions involving the domain have not in J.C. Nature. 1997; 387: 773-776Google Scholar, 9Shibasaki F. Kondo E. Akagi T. McKeon F. Nature. 1997; 386: 728-731Google Scholar, G.P. Li Y. Roth K. Korsmeyer S.J. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 9545-9552Google Scholar, J.C. Cell. 1996; Scholar). To the BH4 domains of BCL-2 and BCL-XL are in specific effects on cell fate and Raf-1 protein we a BCL-2 protein in which the BH4 domain is by the sequence from BCL-XL. This BCL-2 mutant survival D.C.S. J.M. Cory S. EMBO J. 1998; Scholar). A BCL-XL the BCL-2 BH4 domain sequence survival and not be FDCP-Mix cells were stably infected with retrovirus containing BCL2 In to the restricted myeloid differentiation with BCL-2, FDCP-Mix BCL-2 erythroid cells of IL-3 B and that expression of Raf-1 restored in BCL-2 in the presence of IL-3 Cell survival maintained at levels over 5 for IL-3-deprived FDCP-Mix BCL-2 BH4Bcl-x, FDCP-Mix BCL-2, and FDCP-Mix BCL-XL that the specific differentiation effects of the anti-apoptotic proteins are to survival functions The of BCL-2 to cell cycle can also be from its survival by mutations the BH4 (8Huang D.C.S. O'Reilly L.A. Strasser A. Cory S. EMBO J. 1997; 16: 4628-4638Google Scholar). A role for the BCL-2-BH4 domain in Raf-1 protein expression is with this domain a of interactions and supports the that Raf-1 is an of BCL-2 differentiation Expression of Raf-1 FDCP-Mix BCL-2 Cells to Raf-1 a switch for lineage choice in FDCP-Mix cells, we generated FDCP-Mix cell Raf-1 and BCL-2 The introduction of Raf-1 redirected FDCP-Mix BCL-2 cells to an exclusively erythroid fate in analyzed FDCP-Mix cells also expressed in to cells transduced with BCL2 of Raf-1 and BCL-XL not the erythroid associated with FDCP-Mix BCL-XL cells Transduction of by not survival or differentiation of FDCP-Mix cells not However, the addition of a to FDCP-Mix Raf-1 cells erythroid differentiation IL-3 In to the of differentiated cells with BCL-2 or BCL-XL, IL-3-deprived FDCP-Mix cells maintained an in the presence of of a Raf-1, including the catalytic Mol. Cell. Biol. also FDCP-Mix BCL-2 cells to an erythroid fate IL-3 not a mutant of results were accompanied by expression of We expression of the and proteins using a and data not FDCPMix are in We also of Raf-1 using of Raf-1 protein in the were in FDCP-Mix cells. FDCP-Mix cell which erythroid and myeloid lineages, expression of the Raf-1 domain mutant and Raf-1 protein. not with of Raf-1, to the absence of the These results that expression of the domain the of Raf-1 associated with BCL-2 expression, Raf-1 both and proteins expression of Raf-1 Raf-1 is for this an interaction of the Raf-1 domain with the BCL-2-BH4 domain J.C. Cell. 1996; Scholar). domains may act by with interactions between Raf-1 and another BCL-2, of associated a of the role for Raf-1, we the of Raf-1 expression in FDCP-Mix BCL-XL cells. The is for Raf-1 protein and Proc. Exp. Biol. Med. 1998; Scholar, J. 2000; Scholar). with using a specific to of Raf-1 and proteins, and to levels of Raf-1 protein C. L. J. Biol. 1995; Scholar). We FDCP-Mix BCL-XL cells to and of Raf-1 protein expression by h of FDCP-Mix BCL-XL cells the differentiation to IL-3 from erythroid to myeloid with the these the that BCL-2 and BCL-XL differentiation by effects on Raf-1 expression. Cell. previously that FDCP-Mix hematopoietic progenitor cells transduced with BCL2 multilineage differentiation of stochastic or differentiation these in the presence of survival factors, the for specific differentiation signals is In the present we used a to BCL-2 and BCL-XL an to hematopoietic BCL-2 to act on differentiation by cell survival during a However, the a complex between BCL-2-related survival proteins and differentiation, BCL-2 and BCL-XL, the BCL-2 maintain survival of IL-3-deprived FDCP-Mix cells, alternative lineage The of the and multiple that Moreover, and expansion of were performed in the presence of IL-3, that the lineage assays using a to enable of transduced cells Our results of lineage by demonstrating that the survival factors, BCL-XL and BCL-2, are not participants but can also differentiation hematopoietic growth factors the expression of specific BCL-2 family 1996; Scholar, Huang J.J. Blood. 2000; survival and differentiation functions in a single protein a striking of cellular In for expression of proteins previously to with BCL-2 or BCL-XL, we that Raf-1 protein not be in of FDCP-Mix BCL-2 cell FDCP-Mix BCL-2 Raf-1 and each to erythroid cells of Raf-1 protein levels in FDCP-Mix BCL-XL were to cells. FDCP-Mix BCL-XL and FDCP-Mix BCL-2 expressed levels of a level of Raf-1 protein in of 40 FDCP-Mix BCL-XL and this differentiated to myeloid cells IL-3 withdrawal. Thus, in instance, Raf-1 protein is erythroid differentiation and absence of Raf-1 is accompanied by myeloid The of Raf-1 in FDCP-Mix cell fate by that introduction of into FDCP-Mix BCL-2 cells the differentiated from myeloid to erythroid IL-3 withdrawal. This an between Raf-1 and BCL-2, which previously by analysis of FDCP-Mix BCL-2 with differentiation In this is that expression of Raf-1 by with the of erythroid differentiation once IL-3 is of Raf-1 protein in cells is associated with to myeloid Raf-1 and with an active to a switch of FDCP-Mix BCL-2 differentiation from myeloid to erythroid. Thus, the of the Raf-1 appears to be for of erythroid cells. However, both to of Raf-1 protein levels in FDCP-Mix cells. This that the of Raf-1 protein the and that mutant proteins with Raf-1 for binding to another BCL-2, its BH4 is one for this We that a BCL-2 mutant with its BH4 domain by its in BCL-XL not to of Raf-1 expression and that FDCP-Mix cells this BCL-2 are directed to an erythroid fate after IL-3 This BH4 a domain of BCL-2 that both Raf-1 expression and lineage choice and that Raf-1 is an for the BCL-2 differentiation Raf-1 with several protein in including and and to protein and R. J. Biol. Scholar, N. J.H. A. Mol. Cell. Biol. 1999; Scholar). with using to Hsp90, for example, results in of Raf-1 C. L. J. Biol. 1995; Scholar). The domain of Raf-1 is for R. J. Biol. Scholar). the BCL-2-BH4 domain also to the BCL-2 may Raf-1 by its to BCL-2 also with a factor for and H. C. Schneider C. J. Scholar). interactions appear to proteins, binding of to the domain of protein D. J. D. S. J.C. EMBO J. 1998; Scholar, M. M. U. EMBO J. 1997; 16: Scholar). also with the through an to the protein J. J. J. J. Biol. 2000; Scholar). A binding of to BCL-2, in of BCL-2 protein expression S. G. S. Blood. Scholar). Expression of BCL-XL and BCL-2 is by of factors, perhaps expression in hematopoietic cells M. L.M. Cancer Res. Scholar, L. A. P. 16: Scholar). BCL-XL is expressed in and in with levels during erythroid differentiation Blood. 1997; Scholar). hematopoietic cells in and of BCLXL with of erythroid precursors N. F. Roth H. K. K. S. S. 1995; Scholar, E. E.B. G. C. U. L. 2000; Scholar). cells not generate erythroid cells in and, to to in adult mice N. T. T. T. T. J. Exp. Med. 1999; Scholar). BCL-2 is expressed in the B and T and in hematopoietic Expression of a transgene in hematopoietic cells in numbers of lymphocytes and but not and accompanied by a reduction in in the bone S. D. Print C.G. Bath M.L. Harris A.W. J.M. Proc. Natl. Acad. Sci. U. S. A. 1999; Scholar). have that Raf-1 is not expressed in S. J.R. J. J. Biol. Scholar, D. 1995; Scholar). We the absence of Raf-1 in human not whereas Raf-1 by in of cells and differentiation of cells is accompanied by a striking of Raf-1 protein D. 1995; Scholar). Our in FDCP-Mix BCL-2 cells BCL-2 in the of Raf-1 Lineage fate decisions in this may on a for by through Raf-1, which a the cell either by expression of BCL-2 and BCL-XL, and subsequent effects on Raf-1, cell differentiation myeloid and erythroid cell This the effects of BCL-2 and BCL-XL expression on hematopoietic lineage in in and in levels of BCL-2 or BCL-XL, both erythroid and of the be and patterns of differentiation be of the effects of BCL-2, BCL-XL, and BCL-2 into multipotent hematopoietic progenitors may into of lineage restriction during hematopoiesis Y. G. S. E. A. C. Blood. Scholar). We are to for of during the of this and of the We for We also and for and and Boise for
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