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Ref Type Journal Article
PMID (21821710)
Authors Elliott NE, Cleveland SM, Grann V, Janik J, Waldmann TA, Davé UP
Title FERM domain mutations induce gain of function in JAK3 in adult T-cell leukemia/lymphoma.
Journal Blood
Vol 118
Issue 14
Date 2011 Oct 06
URL
Abstract Text Adult T-cell leukemia/lymphoma (ATLL) is an incurable disease where most patients succumb within the first year of diagnosis. Both standard chemotherapy regimens and mAbs directed against ATLL tumor markers do not alter this aggressive clinical course. Therapeutic development would be facilitated by the discovery of genes and pathways that drive or initiate ATLL, but so far amenable drug targets have not been forthcoming. Because the IL-2 signaling pathway plays a prominent role in ATLL pathogenesis, mutational analysis of pathway components should yield interesting results. In this study, we focused on JAK3, the nonreceptor tyrosine kinase that signals from the IL-2R, where activating mutations have been found in diverse neoplasms. We screened 36 ATLL patients and 24 ethnically matched controls and found 4 patients with mutations in JAK3. These somatic, missense mutations occurred in the N-terminal FERM (founding members: band 4.1, ezrin, radixin, and moesin) domain and induced gain of function in JAK3. Importantly, we show that these mutant JAK3s are inhibited with a specific kinase inhibitor already in human clinical testing. Our findings underscore the importance of this pathway in ATLL development and offer a therapeutic handle for this incurable cancer.

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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
JAK3 E183G missense gain of function JAK3 E183G lies within the FERM domain of the Jak3 protein (UniProt.org). E183G confers a gain of function to the Jak3 protein as demonstrated by increased protein stability compared to wild-type, increased Stat5a phosphorylation, and transformation in cultured cells (PMID: 21821710).
JAK3 L156P missense gain of function JAK3 L156P lies within the FERM domain of the Jak3 protein (UniProt.org). L156P results in a gain of function of the Jak3 protein as demonstrated by increased protein stability and transformation in cell culture (PMID: 21821710).
JAK3 R172Q missense gain of function JAK3 R172Q lies within the FERM domain of the Jak3 protein (UniProt.org). R172Q confers a gain of function to the Jak3 protein as demonstrated by constitutive autophosphorylation of Jak3 and increased phosphorylation of Stat5a, and is transforming in cultured cells (PMID: 21821710).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
JAK3 E183G Advanced Solid Tumor sensitive Tofacitinib Preclinical - Cell culture Actionable In a preclinical study, transformed human cells expressing JAK3 E183G in culture demonstrated decreased cell survival, increased G1 arrest, elevated apoptotic activity, and reduced phosphorylation of Stat5a when treated with Xeljanz (tofacitinib) (PMID: 21821710). 21821710
JAK3 A572V Advanced Solid Tumor sensitive Tofacitinib Preclinical - Cell culture Actionable In a preclinical study, transformed human cells expressing JAK3 A572V in culture demonstrated decreased cell survival, increased G1 arrest, elevated apoptotic activity, and reduced phosphorylation of Stat5a when treated with Xeljanz (tofacitinib) (PMID: 21821710). 21821710
JAK3 R172Q Advanced Solid Tumor sensitive Tofacitinib Preclinical - Cell culture Actionable In a preclinical study, transformed human cells expressing JAK3 R172Q in culture demonstrated decreased cell survival, reduced phosphorylation of Stat5a, and G1 arrest when treated with Xeljanz (tofacitinib) (PMID: 21821710). 21821710
JAK3 L156P Advanced Solid Tumor sensitive Tofacitinib Preclinical - Cell culture Actionable In a preclinical study, transformed human cells expressing JAK3 L156P in culture demonstrated decreased cell survival, increased G1 arrest, and reduced phosphorylation of Stat5a when treated with Xeljanz (tofacitinib) (PMID: 21821710). 21821710