TY - JOUR
T1 - Identification of Somatic JAK1 mutations in patients with acute myeloid leukemia
AU - Xiang, Zhifu
AU - Zhao, Yu
AU - Mitaksov, Vesselin
AU - Fremont, Daved H.
AU - Kasai, Yumi
AU - Molitoris, Annalynn
AU - Ries, Rhonda E.
AU - Miner, Tracie L.
AU - McLellan, Michael D.
AU - DiPersio, John F.
AU - Link, Daniel C.
AU - Payton, Jacqueline E.
AU - Graubert, Timothy A.
AU - Watson, Mark
AU - Shannon, William
AU - Heath, Sharon E.
AU - Nagarajan, Rakesh
AU - Mardis, Elaine R.
AU - Wilson, Richard K.
AU - Ley, Timothy J.
AU - Tomasson, Michael H.
PY - 2008/5/1
Y1 - 2008/5/1
N2 - 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 ; JAK1V623A 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.
AB - 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 ; JAK1V623A 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.
UR - http://www.scopus.com/inward/record.url?scp=47149115129&partnerID=8YFLogxK
U2 - 10.1182/blood-2007-05-090308
DO - 10.1182/blood-2007-05-090308
M3 - Article
C2 - 18160671
AN - SCOPUS:47149115129
SN - 0006-4971
VL - 111
SP - 4809
EP - 4812
JO - Blood
JF - Blood
IS - 9
ER -