FERM domain mutations induce gain of function in JAK3 in adult T-cell leukemia/lymphoma

Natalina E. Elliott, Susan M. Cleveland, Victor Grann, John Janik, Thomas A. Waldmann, Utpal P. Davé

Research output: Contribution to journalArticle

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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 inATLL 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.

Original languageEnglish (US)
Pages (from-to)3911-3921
Number of pages11
JournalBlood
Volume118
Issue number14
DOIs
StatePublished - Oct 6 2011

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Adult T Cell Leukemia Lymphoma
T-cells
Mutation
Chemotherapy
Genetic Association Studies
Missense Mutation
Tumor Biomarkers
Protein-Tyrosine Kinases
Interleukin-2
Neoplasms
Phosphotransferases
Genes
Drug Therapy
Testing
Therapeutics
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Immunology
  • Biochemistry
  • Hematology
  • Cell Biology

Cite this

Elliott, N. E., Cleveland, S. M., Grann, V., Janik, J., Waldmann, T. A., & Davé, U. P. (2011). FERM domain mutations induce gain of function in JAK3 in adult T-cell leukemia/lymphoma. Blood, 118(14), 3911-3921. https://doi.org/10.1182/blood-2010-12-319467

FERM domain mutations induce gain of function in JAK3 in adult T-cell leukemia/lymphoma. / Elliott, Natalina E.; Cleveland, Susan M.; Grann, Victor; Janik, John; Waldmann, Thomas A.; Davé, Utpal P.

In: Blood, Vol. 118, No. 14, 06.10.2011, p. 3911-3921.

Research output: Contribution to journalArticle

Elliott, NE, Cleveland, SM, Grann, V, Janik, J, Waldmann, TA & Davé, UP 2011, 'FERM domain mutations induce gain of function in JAK3 in adult T-cell leukemia/lymphoma', Blood, vol. 118, no. 14, pp. 3911-3921. https://doi.org/10.1182/blood-2010-12-319467
Elliott NE, Cleveland SM, Grann V, Janik J, Waldmann TA, Davé UP. FERM domain mutations induce gain of function in JAK3 in adult T-cell leukemia/lymphoma. Blood. 2011 Oct 6;118(14):3911-3921. https://doi.org/10.1182/blood-2010-12-319467
Elliott, Natalina E. ; Cleveland, Susan M. ; Grann, Victor ; Janik, John ; Waldmann, Thomas A. ; Davé, Utpal P. / FERM domain mutations induce gain of function in JAK3 in adult T-cell leukemia/lymphoma. In: Blood. 2011 ; Vol. 118, No. 14. pp. 3911-3921.
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