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 journalArticle

1 Citation (Scopus)

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 1 2014
Externally publishedYes

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Mutation
Janus Kinase 2
Myeloid Progenitor Cells
Myeloproliferative Disorders
Neoplasms
Receptor Protein-Tyrosine Kinases
Dimerization
Hematologic Neoplasms
Point Mutation
Causality
Phosphotransferases
Down-Regulation
Animal Models
Phosphorylation
Phenotype
Immunoglobulin Domains
Therapeutics
In Vitro Techniques
Inhibition (Psychology)
GP 140

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Mutation in the first Ig-Like domain of kit leads to JAK2 activation and myeloproliferation in mice. / Huang, Zan; Ruan, Hai Bin; Zhang, Zeng Di; Chen, Weiqian; Lin, Zhaoyu; Zeng, Hu; Gao, Xiang.

In: American Journal of Pathology, Vol. 184, No. 1, 01.01.2014, p. 122-132.

Research output: Contribution to journalArticle

Huang, Zan ; Ruan, Hai Bin ; Zhang, Zeng Di ; Chen, Weiqian ; Lin, Zhaoyu ; Zeng, Hu ; Gao, Xiang. / Mutation in the first Ig-Like domain of kit leads to JAK2 activation and myeloproliferation in mice. In: American Journal of Pathology. 2014 ; Vol. 184, No. 1. pp. 122-132.
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