TY - JOUR
T1 - A novel activating JAK1 mutation in chronic eosinophilic leukemia
AU - Shomali, William
AU - Damnernsawad, Alisa
AU - Theparee, Talent
AU - Sampson, David
AU - Morrow, Quinlan
AU - Yang, Fei
AU - Fernandez-Pol, Sebastian
AU - Press, Richard
AU - Zehnder, James
AU - Tyner, Jeffrey W.
AU - Gotlib, Jason
N1 - Funding Information:
This work was supported in part by the Stanford Cancer Institute (W.S.), National Institutes of Health, National Heart, Lung, and Blood Institute grant 2T32HL120824-060 (W.S.), the Charles and Ann Johnson Foundation (J.G.), the Mark Foundation for Cancer Research (J.W.T.), the Silver Family Foundation (J.W.T.), and National Institutes of Health, National Cancer Institute grants 1R01CA183947, 1U01CA217862, and 1U54CA224019 (J.W.T.).
Publisher Copyright:
© 2021 by The American Society of Hematology.
PY - 2021/9/28
Y1 - 2021/9/28
N2 - Hypereosinophilia (HE) has been defined as persistent eosinophilia .1.5 3 109/L; it is broadly divided into primary HE (clonal or neoplastic; HEN), secondary/reactive HE (HER), or HE of undetermined significance (HEUS) when no cause is identified. The use of myeloid next-generation sequencing (NGS) panels has led to the detection of several mutations in patients previously diagnosed with HEUS, reassigning some patients to the category of HEN, specifically the World Health Organization category of chronic eosinophilic leukemia, not otherwise specified (CEL, NOS). Here, we describe a novel somatic JAK1 pseudokinase domain mutation (R629_S632delinsSA) in a patient with HE that had initially been characterized as a variant of uncertain significance. We performed functional studies that demonstrated that this mutation results in growth factor independence of Ba/F3 cells in vitro and activation of the JAK-STAT pathway. These effects were abrogated by the JAK1/ JAK2 inhibitor ruxolitinib. R629_S632delinsSA is the first known somatic mutation in JAK1 linked to a clonal eosinophilic neoplasm, and highlights the importance of the JAK-STAT pathway in eosinophil survival.
AB - Hypereosinophilia (HE) has been defined as persistent eosinophilia .1.5 3 109/L; it is broadly divided into primary HE (clonal or neoplastic; HEN), secondary/reactive HE (HER), or HE of undetermined significance (HEUS) when no cause is identified. The use of myeloid next-generation sequencing (NGS) panels has led to the detection of several mutations in patients previously diagnosed with HEUS, reassigning some patients to the category of HEN, specifically the World Health Organization category of chronic eosinophilic leukemia, not otherwise specified (CEL, NOS). Here, we describe a novel somatic JAK1 pseudokinase domain mutation (R629_S632delinsSA) in a patient with HE that had initially been characterized as a variant of uncertain significance. We performed functional studies that demonstrated that this mutation results in growth factor independence of Ba/F3 cells in vitro and activation of the JAK-STAT pathway. These effects were abrogated by the JAK1/ JAK2 inhibitor ruxolitinib. R629_S632delinsSA is the first known somatic mutation in JAK1 linked to a clonal eosinophilic neoplasm, and highlights the importance of the JAK-STAT pathway in eosinophil survival.
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U2 - 10.1182/bloodadvances.2021004237
DO - 10.1182/bloodadvances.2021004237
M3 - Article
C2 - 34496019
AN - SCOPUS:85116103325
SN - 2473-9529
VL - 5
SP - 3581
EP - 3586
JO - Blood advances
JF - Blood advances
IS - 18
ER -