Genetic and pharmacologic evidence implicating the p85α, but not p85β, regulatory subunit of PI3K and Rac2 GTPase in regulating oncogenic KIT-induced transformation in acute myeloid leukemia and systemic mastocytosis

Veerendra Munugalavadla, Emily C. Sims, Jovencio Borneo, Rebecca Chan, Reuben Kapur

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

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 p85α, the regulatory subunit of class IA lipid kinase phosphoinositol-3-kinase (PI3K), but not of p85β, or genetic disruption of the hematopoietic cellspecific Rho GTPase, Rac2, normalizes KITD814V-induced ligand-independent hyperproliferation. Additionally, deficiency of p85α 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.

Original languageEnglish
Pages (from-to)1612-1620
Number of pages9
JournalBlood
Volume110
Issue number5
DOIs
StatePublished - Sep 1 2007

Fingerprint

Systemic Mastocytosis
GTP Phosphohydrolases
Acute Myeloid Leukemia
Phosphotransferases
Hematopoietic Stem Cells
Ligands
Mast Cells
Bearings (structural)
Chemical activation
Cytokines
rho GTP-Binding Proteins
Sirolimus
Stem cells
Cells
Lipids
Cell Line
Mutation
Growth
Therapeutics

ASJC Scopus subject areas

  • Hematology

Cite this

@article{1e0259f359354f139e3709a2232f206d,
title = "Genetic and pharmacologic evidence implicating the p85α, but not p85β, regulatory subunit of PI3K and Rac2 GTPase in regulating oncogenic KIT-induced transformation in acute myeloid leukemia and systemic mastocytosis",
abstract = "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 p85α, the regulatory subunit of class IA lipid kinase phosphoinositol-3-kinase (PI3K), but not of p85β, or genetic disruption of the hematopoietic cellspecific Rho GTPase, Rac2, normalizes KITD814V-induced ligand-independent hyperproliferation. Additionally, deficiency of p85α 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.",
author = "Veerendra Munugalavadla and Sims, {Emily C.} and Jovencio Borneo and Rebecca Chan and Reuben Kapur",
year = "2007",
month = "9",
day = "1",
doi = "10.1182/blood-2006-10-053058",
language = "English",
volume = "110",
pages = "1612--1620",
journal = "Blood",
issn = "0006-4971",
publisher = "American Society of Hematology",
number = "5",

}

TY - JOUR

T1 - Genetic and pharmacologic evidence implicating the p85α, but not p85β, regulatory subunit of PI3K and Rac2 GTPase in regulating oncogenic KIT-induced transformation in acute myeloid leukemia and systemic mastocytosis

AU - Munugalavadla, Veerendra

AU - Sims, Emily C.

AU - Borneo, Jovencio

AU - Chan, Rebecca

AU - Kapur, Reuben

PY - 2007/9/1

Y1 - 2007/9/1

N2 - 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 p85α, the regulatory subunit of class IA lipid kinase phosphoinositol-3-kinase (PI3K), but not of p85β, or genetic disruption of the hematopoietic cellspecific Rho GTPase, Rac2, normalizes KITD814V-induced ligand-independent hyperproliferation. Additionally, deficiency of p85α 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.

AB - 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 p85α, the regulatory subunit of class IA lipid kinase phosphoinositol-3-kinase (PI3K), but not of p85β, or genetic disruption of the hematopoietic cellspecific Rho GTPase, Rac2, normalizes KITD814V-induced ligand-independent hyperproliferation. Additionally, deficiency of p85α 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.

UR - http://www.scopus.com/inward/record.url?scp=34548856481&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=34548856481&partnerID=8YFLogxK

U2 - 10.1182/blood-2006-10-053058

DO - 10.1182/blood-2006-10-053058

M3 - Article

C2 - 17483298

AN - SCOPUS:34548856481

VL - 110

SP - 1612

EP - 1620

JO - Blood

JF - Blood

SN - 0006-4971

IS - 5

ER -