Role of intracellular tyrosines in activating KIT-induced myeloproliferative disease

P. Ma, R. S. Mali, H. Martin, B. Ramdas, E. Sims, Reuben Kapur

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Gain-of-function mutations in KIT receptor in humans are associated with gastrointestinal stromal tumors, systemic mastocytosis and acute myelogenous leukemia. The intracellular signals that contribute to oncogenic KIT-induced myeloproliferative disease (MPD) are poorly understood. Here, we show that oncogenic KITD814V-induced MPD occurs in the absence of ligand stimulation. The intracellular tyrosine residues are important for KITD814V-induced MPD, albeit to varying degrees. Among the seven intracellular tyrosines examined, tyrosine 719 alone has a unique role in regulating KITD814V-induced proliferation and survival in vitro, and MPD in vivo. Importantly, the extent to which AKT, extracellular signal-regulated kinase and Stat5 signaling pathways are activated via the seven intracellular tyrosines in KITD814V impacts the latency of MPD and severity of the disease. Our results identify critical signaling molecules involved in regulating KITD814V-induced MPD, which might be useful for developing novel therapeutic targets for hematologic malignancies involving this mutation.

Original languageEnglish
Pages (from-to)1499-1506
Number of pages8
JournalLeukemia
Volume26
Issue number7
DOIs
StatePublished - Jul 2012

Fingerprint

Tyrosine
Systemic Mastocytosis
Mutation
Gastrointestinal Stromal Tumors
Extracellular Signal-Regulated MAP Kinases
Hematologic Neoplasms
Acute Myeloid Leukemia
Ligands
Survival

Keywords

  • acute myelogenous leukemia (AML)
  • ERK
  • KITD814V
  • PI3Kinase
  • Stat5
  • systemic mastocytosis (SM)

ASJC Scopus subject areas

  • Hematology
  • Cancer Research
  • Anesthesiology and Pain Medicine

Cite this

Role of intracellular tyrosines in activating KIT-induced myeloproliferative disease. / Ma, P.; Mali, R. S.; Martin, H.; Ramdas, B.; Sims, E.; Kapur, Reuben.

In: Leukemia, Vol. 26, No. 7, 07.2012, p. 1499-1506.

Research output: Contribution to journalArticle

Ma, P. ; Mali, R. S. ; Martin, H. ; Ramdas, B. ; Sims, E. ; Kapur, Reuben. / Role of intracellular tyrosines in activating KIT-induced myeloproliferative disease. In: Leukemia. 2012 ; Vol. 26, No. 7. pp. 1499-1506.
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