title: Erlotinib effectively inhibits JAK2V617F activity and polycythemia vera cell growth.
abstract: JAK2(V617F), a mutant of tyrosine kinase JAK2, is found in most patients with polycythemia vera (PV) and a substantial proportion of patients with idiopathic myelofibrosis or essential thrombocythemia. The JAK2 mutant displays a much increased kinase activity and generates a PV-like phenotype in mouse bone marrow transplant models. This study shows that the anti-cancer drug erlotinib (Tarceva) is a potent inhibitor of JAK2(V617F) activity. In vitro colony culture assays revealed that erlotinib at micro-molar concentrations effectively suppresses the growth and expansion of PV hematopoietic progenitor cells while having little effect on normal cells. Furthermore, JAK2(V617F)-positive cells from PV patients show greater susceptibility to the inhibitor than their negative counterparts. Similar inhibitory effects were found with the JAK2(V617F)-positive human erythroleukemia HEL cell line. These data suggest that erlotinib may be used for treatment of JAK2(V617F)-positive PV and other myeloproliferative disorders.
authors.affiliation: Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, USA.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Li
authors.forename: Mingjiang
authors.initials: M
authors.lastname: Xu
authors.forename: Shu
authors.initials: S
authors.lastname: Xing
authors.forename: Wanting Tina
authors.initials: WT
authors.lastname: Ho
authors.forename: Takefumi
authors.initials: T
authors.lastname: Ishii
authors.forename: Qingshan
authors.initials: Q
authors.lastname: Li
authors.forename: Xueqi
authors.initials: X
authors.lastname: Fu
authors.forename: Zhizhuang Joe
authors.initials: ZJ
authors.lastname: Zhao
mesh_terms: D019943:Amino Acid Substitution / Q000235:genetics*; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D016503:Drug Delivery Systems; D004789:Enzyme Activation / Q000187:drug effects / Q000235:genetics; D000069347:Erlotinib Hydrochloride; D006131:Growth Inhibitors / Q000494:pharmacology*; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D006801:Humans; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D019169:Jurkat Cells; D051379:Mice; D010649:Phenylalanine / Q000235:genetics; D011087:Polycythemia Vera / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology*; D014633:Valine / Q000235:genetics
chemical_list: D006131:Growth Inhibitors; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D010649:Phenylalanine; D000069347:Erlotinib Hydrochloride; C507924:JAK2 protein, human; D053614:Janus Kinase 2; D014633:Valine