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J. Exp. Med., Volume 187, Number 12, June 15, 1998 1995-2007

Expression of Constitutively Active Raf-1 in the Mitochondria Restores Antiapoptotic and Leukemogenic Potential of a Transformation-deficient BCR/ABL Mutant

By Paolo Salomoni,*Dagger Mariusz A. Wasik,§ Richard F. Riedel,* Krzysztof Reiss,* John K. Choi,§ Tomasz Skorski,* and Bruno Calabretta*

From the * Department of Microbiology and Immunology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107; the Dagger  Department of Biomedical Sciences, University of Modena, 41100 Modena, Italy; and the § Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19102

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 (p185Delta BCR) 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, p185Delta BCR-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 p185Delta BCR cells was also markedly diminished and mitochondrial RAF was undetectable. In p185Delta BCR 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. p185Delta BCR/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, p185Delta BCR/M-Raf double transfectants were leukemogenic, whereas cells expressing only p185Delta BCR 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.

Key words: oncogene;  signal transduction;  phosphorylation;  apoptosis


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