Requirement for p85α regulatory subunit of class IA PI3K in myeloproliferative disease driven by an activation loop mutant of KIT

Veerendra Munugalavadla, Emily C. Sims, Rebecca Chan, Stephen D. Lenz, Reuben Kapur

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Objective: Oncogenic activation loop mutations of KIT are observed in acute myeloid leukemia (AML) and in myeloproliferative disorders (MPD); however, the signaling pathways that contribute to transformation via these mutations in vivo are not known. Previous studies have demonstrated hyperactivation of p85α regulatory subunit of class IA phosphatidylinositol-3-kinase (PI3K) in cell lines expressing the activation loop mutant of KIT (KITD816V [human] and KITD814V [murine]). Although p85α is hyperphosphorylated and constitutively bound to KITD814V in cell-line models; the physiologic significance of this biochemical phenomenon in KITD814V-induced transformation is not known. Materials and Methods: Here, we describe the generation of a new mouse model to study KITD814V-induced transformation in myeloid cells as opposed to previously described models that primarily result in the generation of disease resembling acute lymphocytic leukemia. Results: Our results show that transplantation of KITD814V expressing bone marrow cells from C57/BL6 strain of mice into syngeneic recipients results in a fatal MPD. Importantly, in this model, transplantation of KITD814V expressing p85α-deficient bone marrow cells rescues the MPD phenotype. Conclusions: Our results describe the generation of a new murine transplant model to study KITD814V-induced transformation and identify p85α as potential therapeutic target for the treatment of KITD814V-bearing diseases.

Original languageEnglish
Pages (from-to)301-308
Number of pages8
JournalExperimental Hematology
Volume36
Issue number3
DOIs
StatePublished - Mar 2008

Fingerprint

Phosphatidylinositol 3-Kinase
Myeloproliferative Disorders
Bone Marrow Cells
Biochemical Phenomena
Transplantation
Cell Line
Mutation
Myeloid Cells
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Acute Myeloid Leukemia
Transplants
Phenotype
Therapeutics

ASJC Scopus subject areas

  • Cancer Research
  • Cell Biology
  • Genetics
  • Hematology
  • Oncology
  • Transplantation

Cite this

Requirement for p85α regulatory subunit of class IA PI3K in myeloproliferative disease driven by an activation loop mutant of KIT. / Munugalavadla, Veerendra; Sims, Emily C.; Chan, Rebecca; Lenz, Stephen D.; Kapur, Reuben.

In: Experimental Hematology, Vol. 36, No. 3, 03.2008, p. 301-308.

Research output: Contribution to journalArticle

@article{9d8964b1b9cd4670b8979d84b7bff314,
title = "Requirement for p85α regulatory subunit of class IA PI3K in myeloproliferative disease driven by an activation loop mutant of KIT",
abstract = "Objective: Oncogenic activation loop mutations of KIT are observed in acute myeloid leukemia (AML) and in myeloproliferative disorders (MPD); however, the signaling pathways that contribute to transformation via these mutations in vivo are not known. Previous studies have demonstrated hyperactivation of p85α regulatory subunit of class IA phosphatidylinositol-3-kinase (PI3K) in cell lines expressing the activation loop mutant of KIT (KITD816V [human] and KITD814V [murine]). Although p85α is hyperphosphorylated and constitutively bound to KITD814V in cell-line models; the physiologic significance of this biochemical phenomenon in KITD814V-induced transformation is not known. Materials and Methods: Here, we describe the generation of a new mouse model to study KITD814V-induced transformation in myeloid cells as opposed to previously described models that primarily result in the generation of disease resembling acute lymphocytic leukemia. Results: Our results show that transplantation of KITD814V expressing bone marrow cells from C57/BL6 strain of mice into syngeneic recipients results in a fatal MPD. Importantly, in this model, transplantation of KITD814V expressing p85α-deficient bone marrow cells rescues the MPD phenotype. Conclusions: Our results describe the generation of a new murine transplant model to study KITD814V-induced transformation and identify p85α as potential therapeutic target for the treatment of KITD814V-bearing diseases.",
author = "Veerendra Munugalavadla and Sims, {Emily C.} and Rebecca Chan and Lenz, {Stephen D.} and Reuben Kapur",
year = "2008",
month = "3",
doi = "10.1016/j.exphem.2007.11.008",
language = "English",
volume = "36",
pages = "301--308",
journal = "Experimental Hematology",
issn = "0301-472X",
publisher = "Elsevier Inc.",
number = "3",

}

TY - JOUR

T1 - Requirement for p85α regulatory subunit of class IA PI3K in myeloproliferative disease driven by an activation loop mutant of KIT

AU - Munugalavadla, Veerendra

AU - Sims, Emily C.

AU - Chan, Rebecca

AU - Lenz, Stephen D.

AU - Kapur, Reuben

PY - 2008/3

Y1 - 2008/3

N2 - Objective: Oncogenic activation loop mutations of KIT are observed in acute myeloid leukemia (AML) and in myeloproliferative disorders (MPD); however, the signaling pathways that contribute to transformation via these mutations in vivo are not known. Previous studies have demonstrated hyperactivation of p85α regulatory subunit of class IA phosphatidylinositol-3-kinase (PI3K) in cell lines expressing the activation loop mutant of KIT (KITD816V [human] and KITD814V [murine]). Although p85α is hyperphosphorylated and constitutively bound to KITD814V in cell-line models; the physiologic significance of this biochemical phenomenon in KITD814V-induced transformation is not known. Materials and Methods: Here, we describe the generation of a new mouse model to study KITD814V-induced transformation in myeloid cells as opposed to previously described models that primarily result in the generation of disease resembling acute lymphocytic leukemia. Results: Our results show that transplantation of KITD814V expressing bone marrow cells from C57/BL6 strain of mice into syngeneic recipients results in a fatal MPD. Importantly, in this model, transplantation of KITD814V expressing p85α-deficient bone marrow cells rescues the MPD phenotype. Conclusions: Our results describe the generation of a new murine transplant model to study KITD814V-induced transformation and identify p85α as potential therapeutic target for the treatment of KITD814V-bearing diseases.

AB - Objective: Oncogenic activation loop mutations of KIT are observed in acute myeloid leukemia (AML) and in myeloproliferative disorders (MPD); however, the signaling pathways that contribute to transformation via these mutations in vivo are not known. Previous studies have demonstrated hyperactivation of p85α regulatory subunit of class IA phosphatidylinositol-3-kinase (PI3K) in cell lines expressing the activation loop mutant of KIT (KITD816V [human] and KITD814V [murine]). Although p85α is hyperphosphorylated and constitutively bound to KITD814V in cell-line models; the physiologic significance of this biochemical phenomenon in KITD814V-induced transformation is not known. Materials and Methods: Here, we describe the generation of a new mouse model to study KITD814V-induced transformation in myeloid cells as opposed to previously described models that primarily result in the generation of disease resembling acute lymphocytic leukemia. Results: Our results show that transplantation of KITD814V expressing bone marrow cells from C57/BL6 strain of mice into syngeneic recipients results in a fatal MPD. Importantly, in this model, transplantation of KITD814V expressing p85α-deficient bone marrow cells rescues the MPD phenotype. Conclusions: Our results describe the generation of a new murine transplant model to study KITD814V-induced transformation and identify p85α as potential therapeutic target for the treatment of KITD814V-bearing diseases.

UR - http://www.scopus.com/inward/record.url?scp=39149093030&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=39149093030&partnerID=8YFLogxK

U2 - 10.1016/j.exphem.2007.11.008

DO - 10.1016/j.exphem.2007.11.008

M3 - Article

C2 - 18179858

AN - SCOPUS:39149093030

VL - 36

SP - 301

EP - 308

JO - Experimental Hematology

JF - Experimental Hematology

SN - 0301-472X

IS - 3

ER -