title: FERM domain mutations induce gain of function in JAK3 in adult T-cell leukemia/lymphoma.
abstract: 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.
authors.affiliation: Departments of Medicine and Cancer Biology, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Natalina E
authors.initials: NE
authors.lastname: Elliott
authors.forename: Susan M
authors.initials: SM
authors.lastname: Cleveland
authors.forename: Victor
authors.initials: V
authors.lastname: Grann
authors.forename: John
authors.initials: J
authors.lastname: Janik
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Waldmann
authors.forename: Utpal P
authors.initials: UP
authors.lastname: Davé
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D004252:DNA Mutational Analysis; D006801:Humans; D053616:Janus Kinase 3 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D050799:STAT5 Transcription Factor / Q000378:metabolism; D016415:Sequence Alignment
chemical_list: D047428:Protein Kinase Inhibitors; D050799:STAT5 Transcription Factor; D053616:Janus Kinase 3