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Molecular and Cellular Biology, August 2004, p. 6993-7002, Vol. 24, No. 16
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.16.6993-7002.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Hematopoietic Cell Fate and the Initiation of Leukemic Properties in Primitive Primary Human Cells Are Influenced by Ras Activity and Farnesyltransferase Inhibition

Craig Dorrell,^1,2, Katsuto Takenaka,¹ Mark D. Minden,³ Robert G. Hawley,⁴ and John E. Dick^1,2*

Department of Molecular and Cellular Biology,¹ Medical Oncology and Hematology, Princess Margaret Hospital,³ Department of Molecular and Medical Genetics, University of Toronto, Toronto, Ontario, Canada,² Holland Laboratory, American Red Cross, Rockville, Maryland⁴

Received 28 October 2003/ Returned for modification 30 December 2003/ Accepted 26 May 2004

The Ras pathway transduces divergent signals determining normal cell fate and is frequently activated in hematopoietic malignancies, but the manner in which activation contributes to human leukemia is poorly understood. We report that a high level of activated H-Ras signaling in transduced primary human hematopoietic progenitors reduced their proliferation and enhanced monocyte/macrophage differentiation. However, the exposure of these cells to a farnesyltransferase inhibitor and establishment of a moderate level of Ras activity showed increased proliferation, an elevated frequency of primitive blast-like cells, and progenitors with enhanced self-renewal capacity. These results suggest that the amplitude of Ras pathway signaling is a determinant of myeloid cell fate and that moderate Ras activation in primitive hematopoietic cells can be an early event in leukemogenesis.

Present address: Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, Oreg.

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