Browsing by Author "Iqbal, Javeed"

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    Enteropathy-associated T cell lymphoma subtypes are characterized by loss of function of SETD2
    (Rockefeller University Press, 2017-05-01) Moffitt, Andrea B.; Ondrejka, Sarah L.; McKinney, Matthew; Rempel, Rachel E.; Goodlad, John R.; Teh, Chun Huat; Leppa, Sirpa; Mannisto, Susanna; Kovanen, Panu E.; Tse, Eric; Au-Yeung, Rex K.H.; Kwong, Yok-Lam; Srivastava, Gopesh; Iqbal, Javeed; Yu, Jiayu; Naresh, Kikkeri; Villa, Diego; Gascoyne, Randy D.; Said, Jonathan; Czader, Magdalena B.; Chadburn, Amy; Richards, Kristy L.; Rajagopalan, Deepthi; Davis, Nicholas S.; Smith, Eileen C.; Palus, Brooke C.; Tzeng, Tiffany J.; Healy, Jane A.; Lugar, Patricia L.; Datta, Jyotishka; Love, Cassandra; Levy, Shawn; Dunson, David B.; Zhuang, Yuan; Hsi, Eric D.; Dave, Sandeep S.; Pathology and Laboratory Medicine, School of Medicine
    Enteropathy-associated T cell lymphoma (EATL) is the most common oncologic complication of celiac disease. Moffitt and colleagues identify novel EATL-defining mutations in SETD2, as well as clinically relevant mutations in the JAK-STAT pathway., Enteropathy-associated T cell lymphoma (EATL) is a lethal, and the most common, neoplastic complication of celiac disease. Here, we defined the genetic landscape of EATL through whole-exome sequencing of 69 EATL tumors. SETD2 was the most frequently silenced gene in EATL (32% of cases). The JAK-STAT pathway was the most frequently mutated pathway, with frequent mutations in STAT5B as well as JAK1, JAK3, STAT3, and SOCS1. We also identified mutations in KRAS, TP53, and TERT. Type I EATL and type II EATL (monomorphic epitheliotropic intestinal T cell lymphoma) had highly overlapping genetic alterations indicating shared mechanisms underlying their pathogenesis. We modeled the effects of SETD2 loss in vivo by developing a T cell–specific knockout mouse. These mice manifested an expansion of γδ T cells, indicating novel roles for SETD2 in T cell development and lymphomagenesis. Our data render the most comprehensive genetic portrait yet of this uncommon but lethal disease and may inform future classification schemes.