Enteropathy-associated T cell lymphoma subtypes are characterized by loss of function of SETD2

Andrea B. Moffitt, Sarah L. Ondrejka, Matthew McKinney, Rachel E. Rempel, John R. Goodlad, Chun Huat Teh, Sirpa Leppa, Susanna Mannisto, Panu E. Kovanen, Eric Tse, Rex K.H. Au-Yeung, Yok Lam Kwong, Gopesh Srivastava, Javeed Iqbal, Jiayu Yu, Kikkeri Naresh, Diego Villa, Randy D. Gascoyne, Jonathan Said, Magdalena B. CzaderAmy Chadburn, Kristy L. Richards, Deepthi Rajagopalan, Nicholas S. Davis, Eileen C. Smith, Brooke C. Palus, Tiffany J. Tzeng, Jane A. Healy, Patricia L. Lugar, Jyotishka Datta, Cassandra Love, Shawn Levy, David B. Dunson, Yuan Zhuang, Eric D. Hsi, Sandeep S. Dave

Research output: Contribution to journalArticle

39 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1371-1386
Number of pages16
JournalJournal of Experimental Medicine
Volume214
Issue number5
DOIs
StatePublished - May 1 2017

Fingerprint

Enteropathy-Associated T-Cell Lymphoma
T-Lymphocytes
Exome
Mutation
T-Cell Lymphoma
Celiac Disease
Knockout Mice

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Moffitt, A. B., Ondrejka, S. L., McKinney, M., Rempel, R. E., Goodlad, J. R., Teh, C. H., ... Dave, S. S. (2017). Enteropathy-associated T cell lymphoma subtypes are characterized by loss of function of SETD2. Journal of Experimental Medicine, 214(5), 1371-1386. https://doi.org/10.1084/jem.20160894

Enteropathy-associated T cell lymphoma subtypes are characterized by loss of function of SETD2. / 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.

In: Journal of Experimental Medicine, Vol. 214, No. 5, 01.05.2017, p. 1371-1386.

Research output: Contribution to journalArticle

Moffitt, AB, Ondrejka, SL, McKinney, M, Rempel, RE, Goodlad, JR, Teh, CH, Leppa, S, Mannisto, S, Kovanen, PE, Tse, E, Au-Yeung, RKH, Kwong, YL, Srivastava, G, Iqbal, J, Yu, J, Naresh, K, Villa, D, Gascoyne, RD, Said, J, Czader, MB, Chadburn, A, Richards, KL, Rajagopalan, D, Davis, NS, Smith, EC, Palus, BC, Tzeng, TJ, Healy, JA, Lugar, PL, Datta, J, Love, C, Levy, S, Dunson, DB, Zhuang, Y, Hsi, ED & Dave, SS 2017, 'Enteropathy-associated T cell lymphoma subtypes are characterized by loss of function of SETD2', Journal of Experimental Medicine, vol. 214, no. 5, pp. 1371-1386. https://doi.org/10.1084/jem.20160894
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. / Enteropathy-associated T cell lymphoma subtypes are characterized by loss of function of SETD2. In: Journal of Experimental Medicine. 2017 ; Vol. 214, No. 5. pp. 1371-1386.
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abstract = "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.",
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AU - Moffitt, Andrea B.

AU - Ondrejka, Sarah L.

AU - McKinney, Matthew

AU - Rempel, Rachel E.

AU - Goodlad, John R.

AU - Teh, Chun Huat

AU - Leppa, Sirpa

AU - Mannisto, Susanna

AU - Kovanen, Panu E.

AU - Tse, Eric

AU - Au-Yeung, Rex K.H.

AU - Kwong, Yok Lam

AU - Srivastava, Gopesh

AU - Iqbal, Javeed

AU - Yu, Jiayu

AU - Naresh, Kikkeri

AU - Villa, Diego

AU - Gascoyne, Randy D.

AU - Said, Jonathan

AU - Czader, Magdalena B.

AU - Chadburn, Amy

AU - Richards, Kristy L.

AU - Rajagopalan, Deepthi

AU - Davis, Nicholas S.

AU - Smith, Eileen C.

AU - Palus, Brooke C.

AU - Tzeng, Tiffany J.

AU - Healy, Jane A.

AU - Lugar, Patricia L.

AU - Datta, Jyotishka

AU - Love, Cassandra

AU - Levy, Shawn

AU - Dunson, David B.

AU - Zhuang, Yuan

AU - Hsi, Eric D.

AU - Dave, Sandeep S.

PY - 2017/5/1

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N2 - 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.

AB - 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.

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