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Blood, 1 September 2007, Vol. 110, No. 5, pp. 1612-1620.
Prepublished online as a Blood First Edition Paper on May 4, 2007; DOI 10.1182/blood-2006-10-053058.
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NEOPLASIA
Genetic and pharmacologic evidence implicating the p85 , but not p85ß, regulatory subunit of PI3K and Rac2 GTPase in regulating oncogenic KIT-induced transformation in acute myeloid leukemia and systemic mastocytosis
Veerendra Munugalavadla1,
Emily C. Sims1,
Jovencio Borneo1,
Rebecca J. Chan1,2, and
Reuben Kapur1,3
1 Department of Pediatrics, Herman B Wells Center for Pediatric Research,
2 Department of Medical and Molecular Genetics, and
3 Department of Molecular Biology and Biochemistry, Indiana University School of Medicine, Indianapolis
Oncogenic activation loop KIT mutations are observed in acute myeloid leukemia (AML) and systemic mastocytosis (SM); however, unlike the KIT juxtamembrane mutants, the activation loop mutants are insensitive to imatinib mesylate. Furthermore, as prior studies primarily used heterologous cell lines, the molecular mechanism(s) underlying oncogenic KIT-induced transformation in primary cells is poorly understood. We demonstrate that expression of KITD814V in primary hematopoietic stem/progenitor cells (HSC/Ps) and mast cell progenitors (MCps) induces constitutive KIT autophosphorylation, supports ligand-independent hyperproliferation, and promotes promiscuous cooperation with multiple cytokines. Genetic disruption of p85 , the regulatory subunit of class IA lipid kinase phosphoinositol-3-kinase (PI3K), but not of p85ß, or genetic disruption of the hematopoietic cell-specific Rho GTPase, Rac2, normalizes KITD814V-induced ligand-independent hyperproliferation. Additionally, deficiency of p85 or Rac2 corrects the promiscuous hyperproliferation observed in response to multiple cytokines in both KITD814V-expressing HSC/Ps and MCps. Treatment of KITD814V-expressing HSC/Ps with a Rac inhibitor (NC23766) or with rapamycin showed a dose-dependent suppression in ligand-independent growth. Taken together, our results identify p85 and Rac2 as potential novel therapeutic targets for the treatment of KITD814V-bearing AML and SM.
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