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. Czader; Amy 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

doi:10.1084/jem.20160894

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

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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.

Original language	English (US)
Pages (from-to)	1371-1386
Number of pages	16
Journal	Journal of Experimental Medicine
Volume	214
Issue number	5
DOIs	https://doi.org/10.1084/jem.20160894
State	Published - May 1 2017

ASJC Scopus subject areas

Medicine(all)

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10.1084/jem.20160894

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Moffitt, A. B., Ondrejka, S. L., McKinney, M., Rempel, R. E., Goodlad, J. R., Teh, C. H., Leppa, S., Mannisto, S., Kovanen, P. E., Tse, E., Au-Yeung, R. K. H., Kwong, Y. L., Srivastava, G., Iqbal, J., Yu, J., Naresh, K., Villa, D., Gascoyne, R. D., Said, J., ... 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

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

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title = "Enteropathy-associated T cell lymphoma subtypes are characterized by loss of function of SETD2",

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.",

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

note = "Publisher Copyright: {\textcopyright} 2017 Moffitt et al.",

year = "2017",

month = may,

day = "1",

doi = "10.1084/jem.20160894",

language = "English (US)",

volume = "214",

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T1 - Enteropathy-associated T cell lymphoma subtypes are characterized by loss of function of SETD2

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

Y1 - 2017/5/1

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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U2 - 10.1084/jem.20160894

DO - 10.1084/jem.20160894

M3 - Article

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AN - SCOPUS:85021853960

SN - 0022-1007

VL - 214

SP - 1371

EP - 1386

JO - Journal of Experimental Medicine

JF - Journal of Experimental Medicine

IS - 5

ER -

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

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