Home | Help | Feedback | Subscriptions | Archive | Search | Table of Contents

This Article Full Text Full Text (PDF, 2186K) PPT slides of all figures Supplemental Material Index Alert me when this article is cited Citation Map Services Email this article Similar articles in this journal Similar articles in PubMed Alert me to new content in the JEM Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Flex, E. Articles by Tartaglia, M. Search for Related Content PubMed PubMed Citation Articles by Flex, E. Articles by Tartaglia, M. Social Bookmarking                      What's this?

¹ Dipartimento di Biologia Cellulare e Neuroscienze, ² Dipartimento di Malattie Infettive, Parassitarie e Immunomediate, Istituto Superiore di Sanità, Rome, 00161, Italy
³ Dipartimento di Scienze e Tecnologie Chimiche, Università "Tor Vergata," Rome, 00133, Italy
⁴ Dipartimento di Biotecnologie Cellulari ed Ematologia, Università "La Sapienza," Rome, 00161, Italy
⁵ Ludwig Institute for Cancer Research and de Duve Institute, Université Catholique de Louvain, Bruxelles, B1200, Belgium
⁶ Département de Génétique, Hôpital Robert Debré, Paris, 75019, France
⁷ Gruppo Italiano Malattie Ematologiche dell'Adulto (GIMEMA) Data Center, GIMEMA Foundation, Rome, 00161, Italy
⁸ Centro Ricerca M. Tettamanti, Clinica Pediatrica Università di Milano Bicocca, Monza, 20052, Italy
⁹ Dipartimento di Medicina Clinica e Sperimentale, Università "Federico II," Napoli, 80131, Italy
¹⁰ Divisione di Ematologia, Università degli Studi di Verona, Verona, 37100, Italy
¹¹ Divisione di Oncologia Pediatrica, Università Cattolica del Sacro Cuore, Rome, 00100, Italy
¹² Departments of Pediatrics and Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, NY 10029

CORRESPONDENCE Marco Tartaglia: mtartaglia{at}iss.it

Aberrant signal transduction contributes substantially to leukemogenesis. The Janus kinase 1 (JAK1) gene encodes a cytoplasmic tyrosine kinase that noncovalently associates with a variety of cytokine receptors and plays a nonredundant role in lymphoid cell precursor proliferation, survival, and differentiation. We report that somatic mutations in JAK1 occur in individuals with acute lymphoblastic leukemia (ALL). JAK1 mutations were more prevalent among adult subjects with the T cell precursor ALL, where they accounted for 18% of cases, and were associated with advanced age at diagnosis, poor response to therapy, and overall prognosis. All mutations were missense, and some were predicted to destabilize interdomain interactions controlling the activity of the kinase. Three mutations that were studied promoted JAK1 gain of function and conferred interleukin (IL)-3–independent growth in Ba/F3 cells and/or IL-9–independent resistance to dexamethasone-induced apoptosis in T cell lymphoma BW5147 cells. Such effects were associated with variably enhanced activation of multiple downstream signaling pathways. Leukemic cells with mutated JAK1 alleles shared a gene expression signature characterized by transcriptional up-regulation of genes positively controlled by JAK signaling. Our findings implicate dysregulated JAK1 function in ALL, particularly of T cell origin, and point to this kinase as a target for the development of novel antileukemic drugs.

E. Flex and V. Petrangeli contributed equally to this paper.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

• Mullighan, C. G., Zhang, J., Harvey, R. C., Collins-Underwood, J. R., Schulman, B. A., Phillips, L. A., Tasian, S. K., Loh, M. L., Su, X., Liu, W., Devidas, M., Atlas, S. R., Chen, I-M., Clifford, R. J., Gerhard, D. S., Carroll, W. L., Reaman, G. H., Smith, M., Downing, J. R., Hunger, S. P., Willman, C. L. (2009). JAK mutations in high-risk childhood acute lymphoblastic leukemia. Proc. Natl. Acad. Sci. USA 106: 9414-9418 [Abstract] [Full Text]  
• Cornejo, M. G., Kharas, M. G., Werneck, M. B., Bras, S. L., Moore, S. A., Ball, B., Beylot-Barry, M., Rodig, S. J., Aster, J. C., Lee, B. H., Cantor, H., Merlio, J.-P., Gilliland, D. G., Mercher, T. (2009). Constitutive JAK3 activation induces lymphoproliferative syndromes in murine bone marrow transplantation models. Blood 113: 2746-2754 [Abstract] [Full Text]  
• Hornakova, T., Staerk, J., Royer, Y., Flex, E., Tartaglia, M., Constantinescu, S. N., Knoops, L., Renauld, J.-C. (2009). Acute Lymphoblastic Leukemia-associated JAK1 Mutants Activate the Janus Kinase/STAT Pathway via Interleukin-9 Receptor {alpha} Homodimers. J. Biol. Chem. 284: 6773-6781 [Abstract] [Full Text]  
• Porcu, M., Gielen, O., Cools, J., De Keersmaecker, K. (2009). JAK1 mutation analysis in T-cell acute lymphoblastic leukemia cell lines. haematol 94: 435-437 [Full Text]  
• Chiaretti, S., Foa, R. (2009). T-cell acute lymphoblastic leukemia. haematol 94: 160-162 [Full Text]  
• Malka, Y., Hornakova, T., Royer, Y., Knoops, L., Renauld, J.-C., Constantinescu, S. N., Henis, Y. I. (2008). Ligand-independent Homomeric and Heteromeric Complexes between Interleukin-2 or -9 Receptor Subunits and the {gamma} Chain. J. Biol. Chem. 283: 33569-33577 [Abstract] [Full Text]  

Home | Help | Feedback | Subscriptions | Archive | Search

TABLE OF CONTENTS