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1.
Front Immunol ; 9: 42, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29416542

RESUMO

A family of transcription factors known as E proteins, and their antagonists, Id proteins, regulate T cell differentiation at critical developmental checkpoints. Id proteins promote the differentiation of conventional αß T cells and suppress the expansion of innate-like αß T cells known as invariant natural killer T (iNKT) cells. However, it remains to be determined whether Id proteins differentially regulate these distinct lineage choices in early stages of T cell development. In this manuscript, we report that in Id-deficient mice, uninhibited activity of the E protein family member E2A mediates activation of genes that support iNKT cell development and function. There is also biased rearrangement in Id-deficient DP cells that promotes selection into the iNKT lineage in these mice. The observed expansion of iNKT cells is not abrogated by blocking pre-TCR signaling, which is required for conventional αß T cell development. Finally, E2A is found to be a key transcriptional regulator of both iNKT and γδNKT lineages, which appear to have shared lineage history. Therefore, our study reveals a previously unappreciated role of E2A in coordinating the development of the iNKT lineage at an early stage, prior to their TCR-mediated selection alongside conventional αß T cells.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/fisiologia , Proteínas Inibidoras de Diferenciação/fisiologia , Células T Matadoras Naturais/fisiologia , Receptores de Antígenos de Linfócitos T/fisiologia , Animais , Diferenciação Celular , Camundongos Knockout
2.
J Exp Med ; 214(5): 1371-1386, 2017 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-28424246

RESUMO

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.


Assuntos
Linfoma de Células T Associado a Enteropatia/fisiopatologia , Histona-Lisina N-Metiltransferase/fisiologia , Animais , Variações do Número de Cópias de DNA/genética , Linfoma de Células T Associado a Enteropatia/classificação , Linfoma de Células T Associado a Enteropatia/genética , Feminino , Perfilação da Expressão Gênica , Inativação Gênica , Humanos , Masculino , Camundongos Knockout , Pessoa de Meia-Idade , Mutação/genética , Análise de Sequência de DNA , Linfócitos T/fisiologia
3.
J Immunol ; 198(8): 3136-3148, 2017 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-28258199

RESUMO

Inhibitor of DNA binding (Id) proteins, including Id1-4, are transcriptional regulators involved in promoting cell proliferation and survival in various cell types. Although upregulation of Id proteins is associated with a broad spectrum of tumors, recent studies have identified that Id3 plays a tumor-suppressor role in the development of Burkitt's lymphoma in humans and hepatosplenic T cell lymphomas in mice. In this article, we report rapid lymphoma development in Id2/Id3 double-knockout mice that is caused by unchecked expansion of invariant NKT (iNKT) cells or a unique subset of innate-like CD1d-independent T cells. These populations began to expand in neonatal mice and, upon malignant transformation, resulted in mortality between 3 and 11 mo of age. The malignant cells also gave rise to lymphomas upon transfer to Rag-deficient and wild-type hosts, reaffirming their inherent tumorigenic potential. Microarray analysis revealed a significantly modified program in these neonatal iNKT cells that ultimately led to their malignant transformation. The lymphoma cells demonstrated chromosome instability along with upregulation of several signaling pathways, including the cytokine-cytokine receptor interaction pathway, which can promote their expansion and migration. Dysregulation of genes with reported driver mutations and the NF-κB pathway were found to be shared between Id2/Id3 double-knockout lymphomas and human NKT tumors. Our work identifies a distinct premalignant state and multiple tumorigenic pathways caused by loss of function of Id2 and Id3. Thus, conditional deletion of Id2 and Id3 in developing T cells establishes a unique animal model for iNKT and relevant innate-like lymphomas.


Assuntos
Proteína 2 Inibidora de Diferenciação/imunologia , Proteínas Inibidoras de Diferenciação/imunologia , Linfoma/imunologia , Células T Matadoras Naturais/imunologia , Subpopulações de Linfócitos T/imunologia , Transferência Adotiva , Animais , Separação Celular , Transformação Celular Neoplásica/imunologia , Transformação Celular Neoplásica/metabolismo , Modelos Animais de Doenças , Citometria de Fluxo , Humanos , Linfoma/patologia , Camundongos , Camundongos Knockout , Análise de Sequência com Séries de Oligonucleotídeos , Reação em Cadeia da Polimerase
4.
Cancer Discov ; 7(4): 369-379, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28122867

RESUMO

Hepatosplenic T-cell lymphoma (HSTL) is a rare and lethal lymphoma; the genetic drivers of this disease are unknown. Through whole-exome sequencing of 68 HSTLs, we define recurrently mutated driver genes and copy-number alterations in the disease. Chromatin-modifying genes, including SETD2, INO80, and ARID1B, were commonly mutated in HSTL, affecting 62% of cases. HSTLs manifest frequent mutations in STAT5B (31%), STAT3 (9%), and PIK3CD (9%), for which there currently exist potential targeted therapies. In addition, we noted less frequent events in EZH2, KRAS, and TP53SETD2 was the most frequently silenced gene in HSTL. We experimentally demonstrated that SETD2 acts as a tumor suppressor gene. In addition, we found that mutations in STAT5B and PIK3CD activate critical signaling pathways important to cell survival in HSTL. Our work thus defines the genetic landscape of HSTL and implicates gene mutations linked to HSTL pathogenesis and potential treatment targets.Significance: We report the first systematic application of whole-exome sequencing to define the genetic basis of HSTL, a rare but lethal disease. Our work defines SETD2 as a tumor suppressor gene in HSTL and implicates genes including INO80 and PIK3CD in the disease. Cancer Discov; 7(4); 369-79. ©2017 AACR.See related commentary by Yoshida and Weinstock, p. 352This article is highlighted in the In This Issue feature, p. 339.


Assuntos
DNA Helicases/genética , Histona-Lisina N-Metiltransferase/genética , Neoplasias Hepáticas/genética , Linfoma de Células T/genética , Neoplasias Esplênicas/genética , Proteína Supressora de Tumor p53/genética , ATPases Associadas a Diversas Atividades Celulares , Adolescente , Adulto , Idoso , Sequência de Bases , Criança , Pré-Escolar , Proteínas de Ligação a DNA , Proteína Potenciadora do Homólogo 2 de Zeste , Exoma/genética , Feminino , Humanos , Neoplasias Hepáticas/complicações , Neoplasias Hepáticas/patologia , Linfoma de Células T/complicações , Linfoma de Células T/patologia , Masculino , Pessoa de Meia-Idade , Proteínas Proto-Oncogênicas p21(ras) , Neoplasias Esplênicas/complicações , Neoplasias Esplênicas/patologia , Fatores de Transcrição , Proteínas Supressoras de Tumor/genética , Adulto Jovem
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