title: Mutation in the first Ig-like domain of Kit leads to JAK2 activation and myeloproliferation in mice.
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.
authors.affiliation: MOE Key Lab of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Nanjing, China.
authors.forename: Zan
authors.initials: Z
authors.lastname: Huang
authors.affiliation: MOE Key Lab of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Nanjing, China.
authors.forename: Hai-Bin
authors.initials: HB
authors.lastname: Ruan
authors.affiliation: Nanjing Children's Hospital Affiliated to Nanjing Medical University, Nanjing, China.
authors.forename: Zeng-Di
authors.initials: ZD
authors.lastname: Zhang
authors.affiliation: MOE Key Lab of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Nanjing, China; Institute for Cardiovascular Science, Soochow University, Suzhou, China; Department of Cardiovascular Surgery, the First Affiliated Hospital of Soochow University, Suzhou, China.
authors.forename: Weiqian
authors.initials: W
authors.lastname: Chen
authors.affiliation: MOE Key Lab of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Nanjing, China.
authors.forename: Zhaoyu
authors.initials: Z
authors.lastname: Lin
authors.affiliation: MOE Key Lab of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Nanjing, China.
authors.forename: Hu
authors.initials: H
authors.lastname: Zeng
authors.affiliation: MOE Key Lab of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Nanjing, China. Electronic address: gaoxiang@nju.edu.cn.
authors.forename: Xiang
authors.initials: X
authors.lastname: Gao
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000235:genetics; D005434:Flow Cytometry; D057809:HEK293 Cells; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D053614:Janus Kinase 2 / Q000378:metabolism*; D051379:Mice; D008817:Mice, Mutant Strains; D009196:Myeloproliferative Disorders / Q000235:genetics* / Q000378:metabolism*; D017354:Point Mutation; D017434:Protein Structure, Tertiary; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics*; D014162:Transfection
chemical_list: D019009:Proto-Oncogene Proteins c-kit; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2