TY - JOUR
T1 - Impact of isolated germline JAK2V617I mutation on human hematopoiesis
AU - Mead, Adam J.
AU - Chowdhury, Onima
AU - Pecquet, Christian
AU - Dusa, Alexandra
AU - Woll, Petter
AU - Atkinson, Deborah
AU - Burns, Adam
AU - Score, Joannah
AU - Rugless, Michelle
AU - Clifford, Ruth
AU - Moule, Simon
AU - Bienz, Nicola
AU - Vyas, Paresh
AU - Cross, Nick
AU - Gale, Rosemary E.
AU - Henderson, Shirley
AU - Constantinescu, Stefan N.
AU - Schuh, Anna
AU - Jacobsen, Sten Eirik W.
N1 - Publisher Copyright:
© 2013 by The American Society of Hematology.
PY - 2013/5/16
Y1 - 2013/5/16
N2 - The association between somatic JAK2 mutation and myeloproliferative neoplasms (MPNs) is now well established. However, because JAK2 mutations are associated with heterogeneous clinical phenotypes and often occur as secondary genetic events, some aspects of JAK2 mutation biology remain to be understood. We recently described a germline JAK2V617I mutation in a family with hereditary thrombocytosis and herein characterize the hematopoietic and signaling impact of JAK2V617I. Through targeted sequencing of MPN-associated mutations, exome sequencing, and clonality analysis, we demonstrate that JAK2V617I is likely to be the sole driver mutation in JAK2V617I-positive individuals with thrombocytosis. Phenotypic hematopoietic stem cells (HSCs) were increased in the blood and bone marrow of JAK2V617I-positive individuals and were sustained at higher levels than controls after xenotransplantation. In signaling and transcriptional assays, JAK2V617I demonstrated more activity than wild-type JAK2 but substantially less than JAK2V617F. After cytokine stimulation, JAK2V617I resulted in markedly increased downstream signaling compared with wild-type JAK2 and comparable with JAK2V617F. These findings demonstrate that JAK2V617I induces sufficient cytokine hyperresponsiveness in the absence of other molecular events to induce a homogeneous MPN-like phenotype. We also provide evidence that the JAK2V617I mutation may expand the HSC pool, providing insights into both JAK2 mutation biology and MPN disease pathogenesis.
AB - The association between somatic JAK2 mutation and myeloproliferative neoplasms (MPNs) is now well established. However, because JAK2 mutations are associated with heterogeneous clinical phenotypes and often occur as secondary genetic events, some aspects of JAK2 mutation biology remain to be understood. We recently described a germline JAK2V617I mutation in a family with hereditary thrombocytosis and herein characterize the hematopoietic and signaling impact of JAK2V617I. Through targeted sequencing of MPN-associated mutations, exome sequencing, and clonality analysis, we demonstrate that JAK2V617I is likely to be the sole driver mutation in JAK2V617I-positive individuals with thrombocytosis. Phenotypic hematopoietic stem cells (HSCs) were increased in the blood and bone marrow of JAK2V617I-positive individuals and were sustained at higher levels than controls after xenotransplantation. In signaling and transcriptional assays, JAK2V617I demonstrated more activity than wild-type JAK2 but substantially less than JAK2V617F. After cytokine stimulation, JAK2V617I resulted in markedly increased downstream signaling compared with wild-type JAK2 and comparable with JAK2V617F. These findings demonstrate that JAK2V617I induces sufficient cytokine hyperresponsiveness in the absence of other molecular events to induce a homogeneous MPN-like phenotype. We also provide evidence that the JAK2V617I mutation may expand the HSC pool, providing insights into both JAK2 mutation biology and MPN disease pathogenesis.
UR - http://www.scopus.com/inward/record.url?scp=84880541262&partnerID=8YFLogxK
U2 - 10.1182/blood-2012-05-430926
DO - 10.1182/blood-2012-05-430926
M3 - Article
C2 - 23535062
AN - SCOPUS:84880541262
SN - 0006-4971
VL - 121
SP - 4156
EP - 4165
JO - Blood
JF - Blood
IS - 20
ER -