The oncogenic BCR/ABL protein protects hematopoietic cells from apoptosis induced by growth factor deprivation, but the mechanisms are only partially understood. A BCR/ABL mutant lacking amino acids 176–426 in the BCR domain (p185ΔBCR) failed to protect interleukin 3–deprived 32Dcl3 myeloid precursor cells from apoptosis, although it possessed tyrosine kinase activity and was capable of activating the Ras-Raf-MAP kinase pathway. Compared to p185 wild-type transfectants, p185ΔBCR-transfected cells showed markedly reduced levels of Bcl-2 and expressed the hypophosphorylated, proapoptotic form of BAD. Bcl-2 expression in the mitochondrial fraction of p185ΔBCR cells was also markedly diminished and mitochondrial RAF was undetectable. In p185ΔBCR cells transfected with a mitochondria-targeted, constitutively active RAF (M-Raf) BAD was expressed in the hyperphosphorylated form and released from the mitochondria into the cytosol. p185ΔBCR/M-Raf–transfected cells were completely resistant to apoptosis induced by growth factor deprivation in vitro. Moreover, constitutive expression of dominant-negative M-Raf (K375W) enhanced the susceptibility of 32Dcl3 cells expressing wild-type BCR/ABL to apoptosis. In severe combined immunodeficiency (SCID) mice, p185ΔBCR/M-Raf double transfectants were leukemogenic, whereas cells expressing only p185ΔBCR showed no leukemogenic potential. Together, these data support the existence of a BCR/ABL-dependent pathway that leads to expression of an active RAF in the mitochondria and promotes antiapoptotic and leukemia-inducing effects of BCR/ABL.
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15 June 1998
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June 15 1998
Expression of Constitutively Active Raf-1 in the Mitochondria Restores Antiapoptotic and Leukemogenic Potential of a Transformation-deficient BCR/ABL Mutant
Paolo Salomoni,
Paolo Salomoni
From the *Department of Microbiology and Immunology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107; the ‡Department of Biomedical Sciences, University of Modena, 41100 Modena, Italy; and the §Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19102
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Mariusz A. Wasik,
Mariusz A. Wasik
From the *Department of Microbiology and Immunology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107; the ‡Department of Biomedical Sciences, University of Modena, 41100 Modena, Italy; and the §Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19102
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Richard F. Riedel,
Richard F. Riedel
From the *Department of Microbiology and Immunology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107; the ‡Department of Biomedical Sciences, University of Modena, 41100 Modena, Italy; and the §Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19102
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Krzysztof Reiss,
Krzysztof Reiss
From the *Department of Microbiology and Immunology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107; the ‡Department of Biomedical Sciences, University of Modena, 41100 Modena, Italy; and the §Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19102
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John K. Choi,
John K. Choi
From the *Department of Microbiology and Immunology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107; the ‡Department of Biomedical Sciences, University of Modena, 41100 Modena, Italy; and the §Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19102
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Tomasz Skorski,
Tomasz Skorski
From the *Department of Microbiology and Immunology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107; the ‡Department of Biomedical Sciences, University of Modena, 41100 Modena, Italy; and the §Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19102
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Bruno Calabretta
Bruno Calabretta
From the *Department of Microbiology and Immunology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107; the ‡Department of Biomedical Sciences, University of Modena, 41100 Modena, Italy; and the §Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19102
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Paolo Salomoni
From the *Department of Microbiology and Immunology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107; the ‡Department of Biomedical Sciences, University of Modena, 41100 Modena, Italy; and the §Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19102
Mariusz A. Wasik
From the *Department of Microbiology and Immunology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107; the ‡Department of Biomedical Sciences, University of Modena, 41100 Modena, Italy; and the §Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19102
Richard F. Riedel
From the *Department of Microbiology and Immunology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107; the ‡Department of Biomedical Sciences, University of Modena, 41100 Modena, Italy; and the §Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19102
Krzysztof Reiss
From the *Department of Microbiology and Immunology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107; the ‡Department of Biomedical Sciences, University of Modena, 41100 Modena, Italy; and the §Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19102
John K. Choi
From the *Department of Microbiology and Immunology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107; the ‡Department of Biomedical Sciences, University of Modena, 41100 Modena, Italy; and the §Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19102
Tomasz Skorski
From the *Department of Microbiology and Immunology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107; the ‡Department of Biomedical Sciences, University of Modena, 41100 Modena, Italy; and the §Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19102
Bruno Calabretta
From the *Department of Microbiology and Immunology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107; the ‡Department of Biomedical Sciences, University of Modena, 41100 Modena, Italy; and the §Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19102
Address correspondence to Bruno Calabretta, Department of Microbiology and Immunology, Kimmel Cancer Center, Thomas Jefferson University, 233 South 10th St., Rm. 630, Philadelphia, PA 19107. Phone: 215-503-4522; Fax: 215-923-0249.
P. Salomoni was supported in part by a postdoctoral fellowship from the University of Modena Medical School, Modena, Italy. T. Skorski was supported in part by R29 CA70815. This work was supported in part by National Institutes of Health and American Cancer Society grants to B. Calabretta.
1
Abbreviations used in this paper: AML, acute myelogenous leukemia; C, cytoplasmic; COX, cytochrome oxidase; CML, chronic myelogenous leukemia; DTT, dithiothreitol; HM, heavy membrane; LM, light membrane; M, mitochondria-targeted; MAP, mitogen-activated protein; MAPK, MAP kinase; MBP, myelin basic protein.
Received:
March 06 1998
Online ISSN: 1540-9538
Print ISSN: 0022-1007
1998
J Exp Med (1998) 187 (12): 1995–2007.
Article history
Received:
March 06 1998
Citation
Paolo Salomoni, Mariusz A. Wasik, Richard F. Riedel, Krzysztof Reiss, John K. Choi, Tomasz Skorski, Bruno Calabretta; Expression of Constitutively Active Raf-1 in the Mitochondria Restores Antiapoptotic and Leukemogenic Potential of a Transformation-deficient BCR/ABL Mutant . J Exp Med 15 June 1998; 187 (12): 1995–2007. doi: https://doi.org/10.1084/jem.187.12.1995
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