{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T17:55:54Z","timestamp":1791309354802,"version":"4.3.1"},"reference-count":28,"publisher":"Rockefeller University Press","issue":"4","content-domain":{"domain":["rupress.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2008,4,14]]},"abstract":"<jats:p>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\u2013independent growth in Ba\/F3 cells and\/or IL-9\u2013independent 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.<\/jats:p>","DOI":"10.1084\/jem.20072182","type":"journal-article","created":{"date-parts":[[2008,3,25]],"date-time":"2008-03-25T00:25:56Z","timestamp":1206404756000},"page":"751-758","update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":292,"title":["Somatically acquired <i>JAK1<\/i> mutations in adult acute lymphoblastic leukemia"],"prefix":"10.1084","volume":"205","author":[{"given":"Elisabetta","family":"Flex","sequence":"first","affiliation":[{"name":"1Dipartimento di Biologia Cellulare e Neuroscienze"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentina","family":"Petrangeli","sequence":"additional","affiliation":[{"name":"1Dipartimento di Biologia Cellulare e Neuroscienze"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lorenzo","family":"Stella","sequence":"additional","affiliation":[{"name":"3Dipartimento di Scienze e Tecnologie Chimiche, Universita\u0300 \u201cTor Vergata,\u201d Rome, 00133, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabina","family":"Chiaretti","sequence":"additional","affiliation":[{"name":"4Dipartimento di Biotecnologie Cellulari ed Ematologia, Universita\u0300 \u201cLa Sapienza,\u201d Rome, 00161, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tekla","family":"Hornakova","sequence":"additional","affiliation":[{"name":"5Ludwig Institute for Cancer Research and de Duve Institute, Universite\u0301 Catholique de Louvain, Bruxelles, B1200, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laurent","family":"Knoops","sequence":"additional","affiliation":[{"name":"5Ludwig Institute for Cancer Research and de Duve Institute, Universite\u0301 Catholique de Louvain, Bruxelles, B1200, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina","family":"Ariola","sequence":"additional","affiliation":[{"name":"4Dipartimento di Biotecnologie Cellulari ed Ematologia, Universita\u0300 \u201cLa Sapienza,\u201d Rome, 00161, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentina","family":"Fodale","sequence":"additional","affiliation":[{"name":"1Dipartimento di Biologia Cellulare e Neuroscienze"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emmanuelle","family":"Clappier","sequence":"additional","affiliation":[{"name":"6De\u0301partement de Ge\u0301ne\u0301tique, Ho\u0302pital Robert Debre\u0301, Paris, 75019, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Paoloni","sequence":"additional","affiliation":[{"name":"7Gruppo Italiano Malattie Ematologiche dell'Adulto (GIMEMA) Data Center, GIMEMA Foundation, Rome, 00161, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simone","family":"Martinelli","sequence":"additional","affiliation":[{"name":"1Dipartimento di Biologia Cellulare e Neuroscienze"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandra","family":"Fragale","sequence":"additional","affiliation":[{"name":"2Dipartimento di Malattie Infettive, Parassitarie e Immunomediate, Istituto Superiore di Sanita\u0300, Rome, 00161, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Massimo","family":"Sanchez","sequence":"additional","affiliation":[{"name":"1Dipartimento di Biologia Cellulare e Neuroscienze"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simona","family":"Tavolaro","sequence":"additional","affiliation":[{"name":"4Dipartimento di Biotecnologie Cellulari ed Ematologia, Universita\u0300 \u201cLa Sapienza,\u201d Rome, 00161, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monica","family":"Messina","sequence":"additional","affiliation":[{"name":"4Dipartimento di Biotecnologie Cellulari ed Ematologia, Universita\u0300 \u201cLa Sapienza,\u201d Rome, 00161, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanni","family":"Cazzaniga","sequence":"additional","affiliation":[{"name":"8Centro Ricerca M. 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