Role of Protein Kinase C Mutations in Adult T-Cell Leukemia

蛋白激酶 C 突变在成人 T 细胞白血病中的作用

• 批准号: 10095197
• 负责人: Lee Ratner
• 金额: $ 18.41万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10095197
• 关键词: Abbreviations; Accounting; Adult T-Cell Leukemia/Lymphoma; Animal Model; Antiviral Agents; Antiviral Therapy; Biochemical; Biological Assay; Biological Markers; Biology; Bone Marrow; Bypass; Caspase; Cell Line; Chemoresistance; Clinic; Clinical; Combination Drug Therapy; Family member; Freezing; Gene Expression Alteration; Gene Targeting; Genes; Growth; Human; Human T-lymphotropic virus 1; IRF4 gene; Immunodeficient Mouse; Individual; Intervention; Label; Laboratories; Lead; Lymphoma cell; Lymphoproliferative Disorders; Malignant Neoplasms; Mature T-Lymphocyte; Mediating; Mediator of activation protein; Modeling; Molecular; Molecular Abnormality; Mus; Mutagens; Mutate; Mutation; Neoplasm Transplantation; Nuclear; Oncogenic; Oncoproteins; PLC gamma1; PTPRC gene; Pathway interactions; Patients; Phase; Protein Inhibition; Protein Kinase C; Protein Kinase C Inhibitor; Receptor Signaling; Recurrence; Refractory; Research; Retroviral Vector; Role; Sampling; Signal Pathway; Signal Transduction; Survival Rate; T Cell Receptor Signaling Pathway; T-Cell Proliferation; T-Cell Receptor; T-Lymphocyte; Testing; Therapeutic; Therapeutic Agents; Translating; Viral; Viral Oncogene; base; design; driver mutation; effective therapy; gain of function mutation; gene product; hematopoietic cell transplantation; improved; in vivo; inhibitor/antagonist; insight; leukemia; model development; mouse model; novel; pilot trial; potential biomarker; protein kinase C beta; receptor; reconstitution; recruit; targeted treatment; therapeutic target; therapeutically effective; tool; transcriptome sequencing; tumorigenesis

Abstract - Role of Protein Kinase C Mutations in Adult T-Cell Leukemia Human T-cell leukemia virus type 1 (HTLV-1) is the cause of a T cell lymphoproliferative disorder, designated adult T-cell leukemia lymphoma (ATL). This is a highly refractory malignancy, lacking effective treatment approaches, with a long-term survival rate of less than four percent. The current project exploits our exciting new discovery of frequent, recurrent mutations in ATL cells in mediators of the T cell receptor (TCR) pathway including phospholipase C γ1 (PLCγ1), protein kinase Cβ (PRKCβ), caspase recruitment domain family member 11 (CARD11), and interferon regulatory factor 4 (IRF4), and resultant nuclear factor κB activation and high level expression of N-Myc. This proposal focuses specifically on possible gain-of-function mutations in PRKCβ in ATL, the most frequent recurrently mutated gene in ATL, with mutation D427N accounting for more than 70% of these PRKCβ mutations. First, we will determine 1) if PRKCβ mutation D427N promotes proliferation of T cells in mice, if T cell proliferation in this setting can be inhibited with PRKCβ inhibitor, midostaurin, and we will identify downstream gene targets of PRKCβ activation in this setting. Second, we will determine if PRKCβ D427N is critical for proliferation of ATL cells in immunodeficient mice, and if ATL growth in mice can be inhibited by midostaurin. We expect this study will provide promising new insights into effective therapy for ATL, which could have relevance to other lymphoproliferative disorders.

蛋白激酶C突变在成人T细胞白血病中的作用 人类T细胞白血病病毒1型（HTLV-1）是T细胞淋巴增生性疾病的原因，称为 成人T细胞白血病淋巴瘤（ATL）。这是一种高度难治的恶性肿瘤，缺乏有效的治疗 长期存活率不到4%。目前的项目利用我们令人兴奋的新 发现ATL细胞中T细胞受体（TCR）通路介导物的频繁复发突变，包括 磷脂酶C γ1（PLCγ1），蛋白激酶Cβ（PRKCβ），caspase募集结构域家族成员11 （CARD 11）和干扰素调节因子4（IRF 4），以及由此产生的核因子κB活化和高水平 N-Myc的表达。该提案特别关注ATL中PRKCβ中可能的功能获得性突变， ATL中最常见的复发突变基因，突变D427 N占这些突变的70%以上 PRKCβ突变。首先，我们将确定1）PRKCβ突变D427 N是否促进小鼠中T细胞的增殖， 如果PRKCβ抑制剂米多替林可以抑制这种情况下的T细胞增殖， 在这种情况下，PRKCβ激活的下游基因靶点。其次，我们将确定PRKCβ D427 N是否是 对于免疫缺陷小鼠中ATL细胞的增殖至关重要，并且如果小鼠中的ATL生长可以通过 米多替林。我们希望这项研究将为ATL的有效治疗提供有希望的新见解， 与其他淋巴增生性疾病相关。