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

蛋白激酶C基因突变在成人T细胞白血病中的作用 人类T细胞白血病病毒1型(HTLV-1)是一种T细胞淋巴增生性疾病的病因，被称为 成人T细胞白血病淋巴瘤(ATL)。这是一种高度难治性的恶性肿瘤，缺乏有效的治疗。 方法，长期存活率不到4%。目前的项目利用了我们激动人心的新技术 在ATL细胞中发现T细胞受体(TCR)途径介体的频繁、反复突变，包括 磷脂酶Cγ1(PLCγ1)、蛋白激酶Cβ(PrKCβ)、半胱氨酸酶招募结构域家族成员11 (CARD11)和干扰素调节因子4(IRF4)，以及由此产生的核因子κB的激活和高水平 N-Myc的表达。该建议特别关注ATL中PrkCβ中可能的功能增益突变， ATL中最常见的反复突变基因，D427N突变占70%以上 PrkCβ突变。首先，我们将确定1)PrkCβ突变D427N是否促进小鼠T细胞的增殖， 如果这种情况下的T细胞增殖可以被PrkCβ抑制剂米哚妥林抑制，我们将确定 在这种情况下，PrKCβ激活的下游基因靶点。其次，我们将确定PRKCβD427N是否 对免疫缺陷小鼠的ATL细胞的增殖至关重要，如果能抑制小鼠的ATL生长 米多妥林。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，这可能 与其他淋巴增生性疾病相关。

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.