c029 activating mutations in jak3 are a common event in adult t

C029
ACTIVATING MUTATIONS IN JAK3 ARE A COMMON EVENT IN ADULT T-CELL LINEAGE ACUTE LYMPHOBLASTIC
LEUKEMIA AND CONCUR WITH JAK1 MUTATIONS TO CONFER POOR PROGNOSIS
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E. Flex , T. Hornakova , V. Fodale , E. Policicchio , E. Stellacci , L. Stella , S. Chiaretti , V. Petrangeli , F. Paoloni , C.
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Carta , A. De Luca , A. Vitale , J. Deng , M. Sanchez , M. Vignetti , G. Cazzaniga , A. Biondi , E.F. Petricoin , R. Foà , J.
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Renauld , M. Tartaglia
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Dip. di Ematologia, Oncologia e Medicina Molecolare, Istituto Superiore di Sanità, Rome, Italy
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Ludwig Institute for Cancer Research and de Duve Institute, Université catholique de Louvain, Bruxelles, Belgium
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Dip. di Scienze e Tecnologie Chimiche, Università “Tor Vergata”, Rome, Italy
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Dip. di Biotecnologie Cellulari ed Ematologia, Università “La Sapienza”, Rome, Italy.
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GIMEMA Data Center, GIMEMA Foundation, Rome, Italy.
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Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA.
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Mendel Laboratory, Casa Sollievo della Sofferenza Hospital, IRCCS, San Giovanni Rotondo, Italy
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Centro Ricerca M. Tettamanti, Clinica Pediatrica Università di Milano Bicocca, Monza, 20052, Italy
Janus kinases (JAKs) are non-receptor protein tyrosine kinases playing a crucial role in cell response to cytokines and
hematopoietic growth factors. While impaired signaling through these proteins is associated with defective lymphoid lineage cell development/function, their acquired enhanced function has been established to contribute to diverse hematologic
malignancies. We previously showed that somatic Janus kinase 1 (JAK1) mutations occur in a subset of patients with T-cell
precursor ALL (T-ALL). Here, we report that somatically acquired gain-of-function mutations in JAK3 represent a relatively
common event in adult T-ALL. JAK3 mutations invariably occurred in T-ALL cases with a JAK1 mutation, identifying a subgroup of patients with poor response to therapy and overall prognosis. Among JAK1 mutation-negative T-ALL, compound
heterozygosity or homozygosity due to uniparental isodisomy for JAK3 lesions are frequently observed. Three mutations
that were studied promoted JAK3 gain of function and conferred IL3-independent growth in Ba/F3 cells. Such effects were
associated with variably enhanced activation of multiple downstream signaling pathways. Our results demonstrate that
aberrant signaling through JAK3 contributes to T-ALL, identify enhanced mTOR activity as a critical pathway for their action,
and point to TOR inhibitors as possible drugs for treatment of JAK3 mutation-associated ALL.