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We found that PRC2 genetic lesions are frequent events in T-ALL and are not restricted to early thymic precursor ALL. PRC2 loss of function associates with activating mutations of the IL7R\/JAK\/STAT pathway. PRC2-altered T-ALL patients respond poorly to prednisone and have low bone marrow blast clearance and persistent minimal residual disease. Furthermore, we identified that PRC2 loss of function profoundly reshapes the genetic and epigenetic landscapes, leading to the reactivation of stem cell programs that cooperate with bromodomain and extraterminal (BET) proteins to sustain T-ALL. This study identifies BET proteins as key mediators of the PRC2 loss of function-induced remodeling. Our data have uncovered a targetable vulnerability to BET inhibition that can be exploited to treat PRC2-altered T-ALL patients.<\/jats:p>","DOI":"10.1182\/blood.2020010081","type":"journal-article","created":{"date-parts":[[2021,6,14]],"date-time":"2021-06-14T15:52:02Z","timestamp":1623685922000},"page":"1855-1869","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":40,"title":["PRC2 loss of function confers a targetable vulnerability to BET proteins in T-ALL"],"prefix":"10.1182","volume":"138","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0289-4952","authenticated-orcid":false,"given":"Guillaume P.","family":"Andrieu","sequence":"first","affiliation":[{"name":"Institut Necker Enfants-Malades, Team 2, INSERM Unit\u00e91151, Paris, France;"},{"name":"H\u00f4pital Necker Enfants-Malades, Laboratoire d\u2019Onco-H\u00e9matologie, Assistance Publique\u2013H\u00f4pitaux de Paris (AP-HP), Paris, France;"},{"name":"Universit\u00e9 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Belgium;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fran\u00e7oise","family":"Huguet","sequence":"additional","affiliation":[{"name":"Institut Universitaire du Cancer, Toulouse, France;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"V\u00e9ronique","family":"Lh\u00e9ritier","sequence":"additional","affiliation":[{"name":"GRAALL Coordination, Hospital Lyon Sud, Pierre-B\u00e9nite, France; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5454-6768","authenticated-orcid":false,"given":"Herv\u00e9","family":"Dombret","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris Diderot, Institut Universitaire d'H\u00e9matologie, EA-3518, Assistance Publique-H\u00f4pitaux de Paris, University Hospital Saint-Louis, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8101-7108","authenticated-orcid":false,"given":"Salvatore","family":"Spicuglia","sequence":"additional","affiliation":[{"name":"Aix-Marseille University, Theories and Approaches of Genomic Complexity (TAGC), INSERM Unit\u00e9 Mixte de Recherche (UMR)1090 13288 Marseille, France;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philippe","family":"Rousselot","sequence":"additional","affiliation":[{"name":"Department of Hematology and Oncology, Centre Hospitalier de Versailles, Le Chesnay, France;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicolas","family":"Boissel","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris Diderot, Institut Universitaire d'H\u00e9matologie, EA-3518, Assistance Publique-H\u00f4pitaux de Paris, University Hospital Saint-Louis, Paris, 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