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c-RAF-1 Serine/Threonine Kinase Is Required in BCR/ABL-dependent and Normal Hematopoiesis¹

Department of Microbiology and Immunology, Jefferson Cancer Institute, Thomas Jefferson University, Philadelphia, Pennsylvania 19107 [T. S., M. N-S., C. S., P. K., D. P., B. P., B. C.]; Lynx Therapeutics, Inc., Hayward, California 94545 [G. Z.]; and Department of Pathology and Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19103 [A. G.]

BCR/ABL oncogenic tyrosine kinase is responsible for initiating and maintaining the leukemic phenotype of Philadelphia chromosome-positive cells. c-RAF-1 serine/threonine kinase is known to be activated by receptor and nonreceptor tyrosine kinases. To determine whether c-RAF-1 plays a role in the growth of BCR/ABL-dependent cells, we examined whether c-RAF-1 associates with and/or is regulated by BCR/ABL and, if so, whether this interaction is functionally significant for BCR/ABL-dependent growth of chronic myelogenous leukemia cells and for growth factor-dependent proliferation of normal bone marrow cells. We show that c-RAF-1 enzymatic activity is regulated by BCR/ABL, although the protein does not associate with BCR/ABL. Downregulation of c-RAF-1 expression with antisense oligodeoxynucleotides or cDNA constructs, and inhibition of c-RAF-1 activity by its dominant negative mutants, inhibited both BCR/ABL-dependent growth of chronic myelogenous leukemia cells and growth factor-dependent proliferation of normal hematopoietic progenitors and the MO7 cell line without affecting the BCR/ABL- and growth factor-independent proliferation of HL-60 cells. These results indicate that c-RAF-1 plays an important role in Philadelphia chromosome-positive and normal hematopoiesis.

¹ Supported in part by American Cancer Society Grant DHP-3B (B. C., T. S.), NHSPS Grants CA 37155 and CA 452884 (B. P.), and T32-CA09678 (P. K.)

² To whom requests for reprints should be addressed, at Department of Microbiology and Immunology, Jefferson Cancer Institute, Thomas Jefferson University, BLSB 630, 233 South 10th Street, Philadelphia, PA 19107.

Received 3/14/95. Accepted 4/20/95.

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