Mutation in the first Ig-Like domain of kit leads to JAK2 activation and myeloproliferation in mice

Zan Huang, Hai Bin Ruan, Zeng Di Zhang, Weiqian Chen, Zhaoyu Lin, Hu Zeng, Xiang Gao

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

Myeloproliferative neoplasms constitute a group of hematopoietic neoplasms at the myeloid stem cell level. Although mutations in the receptor tyrosine kinase KIT have been identified in patients with myeloproliferative neoplasm, the functional causality is unknown because of a lack of animal models. Here, we describe a mouse strain harboring a point mutation in the first Ig-like domain of Kit. Intriguingly, the mutant mice develop a myeloproliferative disorder with typical loss-of-function phenotypes in other tissues. The mutant Kit is incompletely N-glycosylated, shows compromised receptor dimerization, and down-regulates Akt and extracellular signal-regulating kinase 1/2 signaling. However, the mutation increases the association of Kit to Janus kinase (JAK)2 and hence the activation of JAK2. The β common receptor of the gp140 family interacts and synergizes with Kit to promote JAK2 phosphorylation, which is further enhanced by the Kit mutation. Inhibition of JAK2 suppresses the proliferation of hematopoietic progenitors in vitro and partially rescues myeloproliferation in mice. Our data suggest that overactivation of JAK2 leads to myeloproliferation in Kit mutant mice and provide mechanistic insights for the diagnosis and treatment of myeloproliferative neoplasms in humans.

Original languageEnglish (US)
Pages (from-to)122-132
Number of pages11
JournalAmerican Journal of Pathology
Volume184
Issue number1
DOIs
StatePublished - Jan 2014

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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