Identification of somatic JAK1 mutations in patients with acute myeloid leukemia.
Somatic mutations in JAK2 are frequently found in myeloproliferative diseases, and gain-of-function JAK3 alleles have been identified in M7 acute myeloid leukemia (AML), but a role for JAK1 in AML has not been described. We screened the entire coding region of JAK1 by total exonic resequencing of bone marrow DNA samples from 94 patients with de novo AML. We identified 2 novel somatic mutations in highly conserved residues of the JAK1 gene (T478S, V623A), in 2 separate patients and confirmed these by resequencing germ line DNA samples from the same patients. Overexpression of mutant JAK1 did not transform primary murine cells in standard assays, but compared with wild-type JAK1, JAK1(T478S), and JAK1(V623A) expression was associated with increased STAT1 activation in response to type I interferon and activation of multiple downstream signaling pathways. This is the first report to demonstrate somatic JAK1 mutations in AML and suggests that JAK1 mutations may function as disease-modifying mutations in AML pathogenesis.
Xiang
Zhifu
Z
Department of Medicine, Washington University School of Medicine, St Louis, St Louis, MO 63110, USA.
Zhao
Yu
Y
Mitaksov
Vesselin
V
Fremont
Daved H
DH
Kasai
Yumi
Y
Molitoris
AnnaLynn
A
Ries
Rhonda E
RE
Miner
Tracie L
TL
McLellan
Michael D
MD
DiPersio
John F
JF
Link
Daniel C
DC
Payton
Jacqueline E
JE
Graubert
Timothy A
TA
Watson
Mark
M
Shannon
William
W
Heath
Sharon E
SE
Nagarajan
Rakesh
R
Mardis
Elaine R
ER
Wilson
Richard K
RK
Ley
Timothy J
TJ
Tomasson
Michael H
MH
D000818:Animals; D004252:DNA Mutational Analysis; D006801:Humans; D053613:Janus Kinase 1 / Q000235:genetics*; D015470:Leukemia, Myeloid, Acute / Q000209:etiology / Q000235:genetics*; D051379:Mice; D009154:Mutation; D020125:Mutation, Missense; D050794:STAT1 Transcription Factor / Q000378:metabolism; D014161:Transduction, Genetic
D050794:STAT1 Transcription Factor; C507904:JAK1 protein, human; D053613:Janus Kinase 1