Rac guanosine triphosphatases represent integrating molecular therapeutic targets for BCR-ABL-induced myeloproliferative disease

Cancer Cell. 2007 Nov;12(5):467-78. doi: 10.1016/j.ccr.2007.10.015.

Abstract

Chronic myelogenous leukemia (CML) is a clonal myeloproliferative disease (MPD) initiated by expression of the p210-BCR-ABL fusion protein. We demonstrate in a murine model of p210-BCR-ABL-induced MPD that gene targeting of Rac1 and Rac2 significantly delays or abrogates disease development. Attenuation of the disease phenotype is associated with severely diminished p210-BCR-ABL-induced downstream signaling in primary hematopoietic cells. We utilize NSC23766, a small molecule antagonist of Rac activation, to validate biochemically and functionally Rac as a molecular target in both a relevant animal model and in primary human CML cells in vitro and in a xenograft model in vivo, including in Imatinib-resistant p210-BCR-ABL disease. These data demonstrate that Rac is an additional therapeutic target in p210-BCR-ABL-mediated MPD.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Aminoquinolines / pharmacology
  • Animals
  • Antigens, CD34 / biosynthesis
  • Cell Line, Tumor
  • Dose-Response Relationship, Drug
  • Fusion Proteins, bcr-abl / metabolism*
  • Gene Expression Regulation, Leukemic*
  • Hematopoietic Stem Cells / metabolism
  • Humans
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / metabolism*
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / therapy
  • Mice
  • Myeloproliferative Disorders / genetics*
  • Myeloproliferative Disorders / metabolism*
  • Myeloproliferative Disorders / therapy
  • Neoplasm Transplantation
  • Phenotype
  • Pyrimidines / pharmacology
  • rac GTP-Binding Proteins / metabolism
  • rac GTP-Binding Proteins / physiology*
  • rac1 GTP-Binding Protein / metabolism

Substances

  • Aminoquinolines
  • Antigens, CD34
  • NSC 23766
  • Pyrimidines
  • RAC1 protein, human
  • Fusion Proteins, bcr-abl
  • rac2 GTP-binding protein
  • rac GTP-Binding Proteins
  • rac1 GTP-Binding Protein