Expression of a homodimeric type I cytokine receptor is required for JAK2V617F-mediated transformation.
A recurrent somatic activating mutation in the nonreceptor tyrosine kinase JAK2 (JAK2V617F) occurs in the majority of patients with the myeloproliferative disorders polycythemia vera, essential thrombocythemia, myelofibrosis with myeloid metaplasia, and, less commonly, chronic myelomonocytic leukemia. We do not understand the basis for the specificity of the JAK2V617F mutation in clonal disorders of the myeloid, but not lymphoid, lineage, nor has the basis for the pleiotropic phenotype of JAK2V617F-associated myeloproliferative disorders been delineated. However, the presence of the identical mutation in patients with related, but clinicopathologically distinct, myeloid disorders suggests that interactions between the JAK2V617F kinase and other signaling molecules may influence the phenotype of hematopoietic progenitors expressing JAK2V617F. Here, we show that coexpression of the JAK2V617F mutant kinase with a homodimeric Type I cytokine receptor, the erythropoietin receptor (EpoR), the thrombopoietin receptor, or the granulocyte colony-stimulating-factor receptor, is necessary for transformation of hematopoietic cells to growth-factor independence and for hormone-independent activation of JAK-STAT signaling. Furthermore, EpoR mutations that impair erythropoietin-mediated JAK2 or STAT5 activation also impair transformation mediated by the JAK2V617F kinase, indicating that JAK2V617F requires a cytokine receptor scaffold for its transforming and signaling activities. Our results reveal the molecular basis for the prevalence of JAK2V617F in diseases of myeloid lineage cells that express these Type I cytokine receptors but not in lymphoid lineage cells that do not.
Lu
Xiaohui
X
Whitehead Institute for Biomedical Research and the Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
Levine
Ross
R
Tong
Wei
W
Wernig
Gerlinde
G
Pikman
Yana
Y
Zarnegar
Sara
S
Gilliland
D Gary
DG
Lodish
Harvey
H
D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D019070:Cell Lineage; D016207:Cytokines / Q000378:metabolism; D019281:Dimerization; D006412:Hematopoietic Stem Cells / Q000166:cytology; D006801:Humans; D047468:Immunoprecipitation; D053614:Janus Kinase 2; D051379:Mice; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D009196:Myeloproliferative Disorders; D015513:Oncogene Proteins / Q000378:metabolism; D010641:Phenotype; D017434:Protein Structure, Tertiary; D011505:Protein-Tyrosine Kinases / Q000737:chemistry* / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000737:chemistry* / Q000235:genetics*; D018121:Receptors, Cytokine / Q000378:metabolism; D017467:Receptors, Erythropoietin / Q000378:metabolism; D053628:Receptors, Thrombopoietin; D012190:Retroviridae / Q000235:genetics; D015398:Signal Transduction; D013997:Time Factors
D016207:Cytokines; C481270:Mpl protein, mouse; D015513:Oncogene Proteins; D011518:Proto-Oncogene Proteins; D018121:Receptors, Cytokine; D017467:Receptors, Erythropoietin; D053628:Receptors, Thrombopoietin; D011505:Protein-Tyrosine Kinases; C507924:JAK2 protein, human; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2