Hematopoietic cell fate and the initiation of leukemic properties in primitive primary human cells are influenced by Ras activity and farnesyltransferase inhibition

Craig Dorrell, Katsuto Takenaka, Mark D. Minden, Robert G. Hawley, John E. Dick

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)6993-7002
Number of pages10
JournalMolecular and cellular biology
Volume24
Issue number16
DOIs
Publication statusPublished - Aug 2004

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

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