A novel activating JAK1 mutation in chronic eosinophilic leukemia

被引：12

作者：

Shomali, William ^{[1
]}

Damnernsawad, Alisa ^{[2
,3
]}

Theparee, Talent ^{[4
]}

Sampson, David ^{[2
]}

Morrow, Quinlan ^{[2
]}

Yang, Fei ^{[5
,6
]}

Fernandez-Pol, Sebastian ^{[7
]}

Press, Richard ^{[5
,6
]}

Zehnder, James ^{[1
,7
]}

Tyner, Jeffrey W. ^{[2
,8
]}

Gotlib, Jason ^{[1
]}

机构：

[1] Stanford Univ, Sch Med, Stanford Canc Inst, Div Hematol, Stanford, CA 94305 USA

[2] Oregon Hlth & Sci Univ, Dept Cell Dev & Canc Biol, Portland, OR 97201 USA

[3] Mahidol Univ, Fac Sci, Dept Biol, Bangkok, Thailand

[4] Univ Calif San Francisco, Dept Pathol, San Francisco, CA 94143 USA

[5] Oregon Hlth & Sci Univ, Dept Pathol, Portland, OR 97201 USA

[6] Oregon Hlth & Sci Univ, Knight Canc Inst, Portland, OR 97201 USA

[7] Stanford Univ, Sch Med, Dept Pathol, Stanford, CA 94305 USA

[8] Oregon Hlth & Sci Univ, Div Hematol & Med Oncol, Portland, OR 97201 USA

来源：

BLOOD ADVANCES | 2021年 / 5卷 / 18期

基金：

美国国家卫生研究院;

关键词：

KINASE; SENSITIVITY; RESISTANCE;

D O I：

10.1182/bloodadvances.2021004237

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Hypereosinophilia (HE) has been defined as persistent eosinophilia >1.5 x 10(9)/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.

引用

页码：3581 / 3586

页数：6

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