Cooperative role of TET2 and IDH2 mutations in angioimmunoblastic T-cell lymphomagenesis

TET2 和 IDH2 突变在血管免疫母细胞 T 细胞淋巴瘤发生中的协同作用

• 批准号: 10672370
• 负责人: Wing C. Chan
• 金额: $ 47.86万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10672370
• 关键词: Affect; Aggressive Clinical Course; Arginine; CD28 gene; CD4 Positive T Lymphocytes; CRISPR/Cas technology; Cell Differentiation process; Cell Line; Cell model; Cells; Characteristics; Clinical; Clonal Expansion; DNA; DNA Methylation; DNMT3a; Development; Diagnosis; Enzymes; Epigenetic Process; Event; Family member; Gene Expression; Gene Expression Profiling; Gene Mutation; Genes; Genetic; Genomics; Glutamine; Goals; Helper-Inducer T-Lymphocyte; Hematologic Neoplasms; Hematopoiesis; Hematopoietic stem cells; Human; Immunoblastic Lymphadenopathy; Immunophenotyping; In Vitro; Induced Mutation; Knockout Mice; Lesion; Lymphoma; Lymphomagenesis; Malignant - descriptor; Malignant lymphoid neoplasm; Mediating; Metabolic; Modification; Molecular; Mus; Mutation; Myeloid Cells; Myeloproliferative disease; Oncogenic; Outcome; Pathogenesis; Pathogenicity; Pathologic; Pathway interactions; Patients; Peripheral; Phenotype; Play; Pre-Clinical Model; Preclinical Testing; Production; RHOA gene; Research; Role; Sampling; Specimen; Stromal Cells; System; T cell differentiation; T-Cell Activation; T-Cell Development; T-Cell Lymphoma; T-Cell Transformation; T-Lymphocyte; Testing; Therapeutic Intervention; Transgenic Organisms; Validation; accurate diagnosis; cell transformation; demethylation; disease prognosis; drug efficacy; effective therapy; efficacy study; efficacy testing; epigenome; epigenomics; genome-wide; histone demethylase; human model; inhibitor; insight; loss of function mutation; mouse model; mutant; mutant mouse model; neoplastic; neoplastic cell; novel; novel therapeutic intervention; novel therapeutics; patient derived xenograft model; polarized cell; pre-clinical; programs; targeted treatment; therapeutic evaluation; treatment response; tumor; tumor microenvironment

Abstract Angioimmunoblastic T-cell lymphoma (AITL) is the most common subtype of peripheral T-cell lymphoma (PTCL) with distinct pathological and clinical characteristics. It is a difficult-to-diagnose and lacks effective therapies due to poor understanding of the molecular pathogenesis. Using genome-wide gene expression profiling (GEP), we have defined a robust molecular classifier for accurate diagnosis, identified oncogenic pathways, discovered its cell-of-origin, and deciphered the role of the tumor milieu in disease prognosis. Using high-throughput genomic analysis, we also identified frequent mutations in epigenetic regulators (TET2, IDH2 and DNMT3A) and regulators of T-cell activation (RHOA and CD28) in AITL. Co-occurrence of TET2 mutations with IDH2 mutation (hotspot: arginine-172; IDH2R172) is unique in AITL compared to other hematological malignancies where they are mutually exclusive, suggesting their cooperative role in T-cell lymphomagenesis. We have generated unique murine models with conditional loss of Tet2 (Tet2-/-) and double mutant (Tet2-/- /IDH2R172K) in CD4+ T-cells, and murine lymphomas with follicular helper T-cell (TFH) phenotype were observed. In addition, we generated several patient-derived xenografts (PDX) of AITL with IDH2R172 and/or TET2 mutations. We hypothesize that TET2 deficiency in T cells alters the DNA methylation profile leading to an altered genetic program favoring TFH cell differentiation and clonal expansion, facilitating transformation with subsequent hits, including IDH2R172 mutation, which will further alter the epigenome and oncogenic pathways in TFH -cell transformation. We will define the precise role of these genetic lesions in T-cell differentiation and in AITL pathogenesis. We also edited normal human CD4+ T-cells using CRISPR/CAS9 to generate TET2-/- T-cells for functional analysis and cross-validation of murine models. SinceTET2 mutations are in hematopoietic stem/progenitor cells (HSPC) in some AITLs, interactions between TET2 deficient T- and stromal cells during lymphomagenesis will be explored. We will test the efficacy of therapeutic interventions, including demethylating agents for TET2 deficiency and IDH2 inhibitors and/or glutamine depletion for TET2/IDH2 double mutant tumors in murine models and PDX of AITL. To accomplish the objective, three aims are planned: Specific Aim 1: To determine the mechanisms by which Tet2 deficiency mediates T-cell transformation and the role of Tet2 mutation in stromal cells in lymphomagenesis. Specific Aim 2: To delineate the mechanisms of combined Tet2 and IDH2R172K mutations in AITL pathogenesis. Specific Aim 3: To evaluate therapies targeting oncogenic mechanisms mediated by Tet2 and IDH2R172 mutations. Our long-term research goal is to define the pathobiology of AITL, through integrated functional epigenomic approaches using in vitro modified human T-cells, patient samples and relevant murine models, thus identifying promising novel targets for treatment that may be tested pre-clinically in PDX models.

摘要