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.

journal_name

Blood

journal_title

Blood

authors

Elliott NE,Cleveland SM,Grann V,Janik J,Waldmann TA,Davé UP

doi

10.1182/blood-2010-12-319467

subject

Has Abstract

pub_date

2011-10-06 00:00:00

pages

3911-21

issue

14

eissn

0006-4971

issn

1528-0020

pii

blood-2010-12-319467

journal_volume

118

pub_type

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