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Ref Type Journal Article
PMID (34496019)
Authors Shomali W, Damnernsawad A, Theparee T, Sampson D, Morrow Q, Yang F, Fernandez-Pol S, Press R, Zehnder J, Tyner JW, Gotlib J
Title A novel activating JAK1 mutation in chronic eosinophilic leukemia.
Journal Blood advances
Vol 5
Issue 18
Date 2021 Sep 28
URL
Abstract Text Hypereosinophilia (HE) has been defined as persistent eosinophilia >1.5 × 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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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
JAK1 R629_S632delinsSA indel gain of function JAK1 R629_S632delinsSA results in a deletion of four amino acids in the protein kinase domain 1 of the Jak1 protein from amino acids 629 to 632, combined with the insertion of a serine (S) and an alanine (A) at the same site (UniProt.org). R629_S632delinsSA confers a gain of function to the Jak1 protein as demonstrated by increased Stat3 and Stat5 phosphorylation in cultured cells, and is transforming in culture (PMID: 34496019).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
JAK1 R629_S632delinsSA hypereosinophilic syndrome predicted - sensitive Tofacitinib Preclinical - Patient cell culture Actionable In a preclinical study, Xeljanx (tofacitinib) treatment resulted in decreased viability of blood and marrow cells derived from a patient with hypereosinophilia harboring JAK1 R629_S632delinsSA in culture (PMID: 34496019). 34496019
JAK1 R629_S632delinsSA hypereosinophilic syndrome predicted - resistant Ruxolitinib Preclinical - Patient cell culture Actionable In a preclinical study, blood and marrow cells derived from a patient with hypereosinophilia harboring JAK1 R629_S632delinsSA were resistant to Jakafi (ruxolitinib) treatment in culture (PMID: 34496019). 34496019
JAK1 A634D hematologic cancer sensitive Tofacitinib Preclinical - Cell culture Actionable In a preclinical study, Xeljanz (tofacitinib) treatment resulted in decreased viability of transformed cells expressing JAK1 A634D in culture (PMID: 34496019). 34496019
JAK1 A634D hematologic cancer sensitive Ruxolitinib Preclinical - Cell culture Actionable In a preclinical study, Jakafi (ruxolitinib) treatment inhibited Stat5 signaling and decreased viability of transformed cells expressing JAK1 A634D in culture (PMID: 34496019). 34496019
JAK1 R629_S632delinsSA hematologic cancer sensitive Ruxolitinib Preclinical - Cell culture Actionable In a preclinical study, Jakafi (ruxolitinib) treatment inhibited Stat5 signaling and decreased viability of transformed cells expressing JAK1 R629_S632delinsSA in culture (PMID: 34496019). 34496019
JAK1 R629_S632delinsSA hematologic cancer sensitive Tofacitinib Preclinical - Cell culture Actionable In a preclinical study, Xeljanz (tofacitinib) treatment resulted in decreased viability of transformed cells expressing JAK1 R629_S632delinsSA in culture (PMID: 34496019). 34496019