Reference Detail

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	Vol	Issue	Date	Pages	Journal Short Title
Blood advances	5	18	2021 Sep 28	3581-3586	Blood Adv

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	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
JAK1 R629_S632delinsSA	hypereosinophilic syndrome	predicted - sensitive	Tofacitinib	Preclinical - Patient cell culture	Actionable	In a preclinical study, Xeljanz (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