title: Activating alleles of JAK3 in acute megakaryoblastic leukemia.
abstract: Tyrosine kinases are aberrantly activated in numerous malignancies, including acute myeloid leukemia (AML). To identify tyrosine kinases activated in AML, we developed a screening strategy that rapidly identifies tyrosine-phosphorylated proteins using mass spectrometry. This allowed the identification of an activating mutation (A572V) in the JAK3 pseudokinase domain in the acute megakaryoblastic leukemia (AMKL) cell line CMK. Subsequent analysis identified two additional JAK3 alleles, V722I and P132T, in AMKL patients. JAK3(A572V), JAK3(V722I), and JAK3(P132T) each transform Ba/F3 cells to factor-independent growth, and JAK3(A572V) confers features of megakaryoblastic leukemia in a murine model. These findings illustrate the biological importance of gain-of-function JAK3 mutations in leukemogenesis and demonstrate the utility of proteomic approaches to identifying clinically relevant mutations.
authors.affiliation: Howard Hughes Medical Institute, Portland, Oregon 97239, USA.
authors.forename: Denise K
authors.initials: DK
authors.lastname: Walters
authors.forename: Thomas
authors.initials: T
authors.lastname: Mercher
authors.forename: Ting-Lei
authors.initials: TL
authors.lastname: Gu
authors.forename: Thomas
authors.initials: T
authors.lastname: O'Hare
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Tyner
authors.forename: Marc
authors.initials: M
authors.lastname: Loriaux
authors.forename: Valerie L
authors.initials: VL
authors.lastname: Goss
authors.forename: Kimberly A
authors.initials: KA
authors.lastname: Lee
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Eide
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Wong
authors.forename: Eric P
authors.initials: EP
authors.lastname: Stoffregen
authors.forename: Laura
authors.initials: L
authors.lastname: McGreevey
authors.forename: Julie
authors.initials: J
authors.lastname: Nardone
authors.forename: Sandra A
authors.initials: SA
authors.lastname: Moore
authors.forename: John
authors.initials: J
authors.lastname: Crispino
authors.forename: Titus J
authors.initials: TJ
authors.lastname: Boggon
authors.forename: Michael C
authors.initials: MC
authors.lastname: Heinrich
authors.forename: Michael W
authors.initials: MW
authors.lastname: Deininger
authors.forename: Roberto D
authors.initials: RD
authors.lastname: Polakiewicz
authors.forename: D Gary
authors.initials: DG
authors.lastname: Gilliland
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Druker
mesh_terms: D000483:Alleles; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D000068877:Imatinib Mesylate; D053614:Janus Kinase 2; D053616:Janus Kinase 3; D020014:K562 Cells; D007942:Leukemia, Experimental / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D007947:Leukemia, Megakaryoblastic, Acute / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D050505:Mutant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017434:Protein Structure, Tertiary / Q000235:genetics; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics; D053634:TYK2 Kinase
chemical_list: D001549:Benzamides; D050505:Mutant Proteins; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D011743:Pyrimidines; D034741:RNA, Small Interfering; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; C507924:JAK2 protein, human; C507933:JAK3 protein, human; C507926:Jak2 protein, mouse; C507935:Jak3 protein, mouse; D053614:Janus Kinase 2; D053616:Janus Kinase 3; D053634:TYK2 Kinase; C070139:TYK2 protein, human