Activating alleles of JAK3 in acute megakaryoblastic leukemia.
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.
Walters
Denise K
DK
Howard Hughes Medical Institute, Portland, Oregon 97239, USA.
Mercher
Thomas
T
Gu
Ting-Lei
TL
O'Hare
Thomas
T
Tyner
Jeffrey W
JW
Loriaux
Marc
M
Goss
Valerie L
VL
Lee
Kimberly A
KA
Eide
Christopher A
CA
Wong
Matthew J
MJ
Stoffregen
Eric P
EP
McGreevey
Laura
L
Nardone
Julie
J
Moore
Sandra A
SA
Crispino
John
J
Boggon
Titus J
TJ
Heinrich
Michael C
MC
Deininger
Michael W
MW
Polakiewicz
Roberto D
RD
Gilliland
D Gary
DG
Druker
Brian J
BJ
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
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