Inhibition of T-cell Receptor Signaling for Treatment of Adult T-cell Leukemia Lymphoma

摘要-抑制T细胞受体信号传导治疗成人T细胞白血病淋巴瘤 人类T细胞白血病病毒1型（HTLV-1）相关的成人T细胞白血病淋巴瘤（ATLL）是一种恶性肿瘤。 侵袭性淋巴增生性恶性肿瘤尽管积极的化疗，这种疾病是致命的，几乎所有 个体我们和其他人的初步结果发现，T细胞受体的突变率很高， (TCR)ATLL中的信号通路，磷脂酶Cγ、蛋白激酶Cβ（PKCβ）和 半胱天冬酶募集结构域蛋白11（CARD 11）导致转录因子核激活 因子κB（NFκB）和干扰素调节因子4（IRF 4）。我们假设这条通路驱动ATLL 针对该途径的靶向治疗将与联合治疗协同作用。 化疗我们还认为来那度胺抑制ATLL中IRF 4的表达。我们建议评估： 目的1：通过RNAseq和IRF 4依赖基因的功能分析，研究IRF 4激活在ATLL中的作用 目标的我们还将确定IRF 4的抑制是否介导来那度胺在ATLL中的细胞毒性作用。 目的2：来那度胺联合EPOCH化疗治疗HTLV-ATLL的I期研究 通过ETCTN进行，并在当前项目中进行相关研究，以评估是否 来那度胺疗效通过对IRF 4的作用介导，并取决于TCR途径中的突变 件.将使用HTLV负荷、表达和克隆性测定来监测治疗的疗效。 目的3：PKCβ激活在ATLL中的作用将作为一种替代治疗靶点进行研究， ATLL细胞对抑制剂恩扎鲁肽和米多鲁肽的敏感性。我们将评估是否敏感这些 抑制剂受PKCβ或CARD 11突变的影响，这些突变通常在ATLL中共同发生。 这项研究将提供深入了解TCR信号传导在ATLL中的作用，以及新的治疗靶点。

Abstract – Inhibition of T-Cell Receptor Signaling for Treatment of Adult T-Cell Leukemia Lymphoma Human T-cell leukemia virus type 1 (HTLV-1)-associated adult T-cell leukemia-lymphoma (ATLL) is an aggressive lymphoproliferative malignancy. Despite aggressive chemotherapy, this disorder is fatal in almost all individuals. Our preliminary results, and those of others, uncovered a high rate of mutations in the T-cell receptor (TCR) signaling pathway in ATLL, with frequent mutations in phospholipase Cγ, protein kinase Cβ (PKCβ), and caspase recruitment domain containing protein 11 (CARD11) leading to activation of transcription factors nuclear factor κB (NFκB) and interferon-regulatory factor 4 (IRF4). We hypothesize that this pathway drives ATLL development and/or progression and targeted therapy against this pathway will synergize with combination chemotherapy. We also suggest that lenalidomide represses IRF4 expression in ATLL. We propose to assess: Aim 1: Role of IRF4 activation in ATLL through RNAseq and functional analysis of IRF4-dependent gene targets. We will also determine if repression of IRF4 mediates the cytotoxic effects of lenalidomide in ATLL. Aim 2: Phase 1 study of lenalidomide in combination with EPOCH chemotherapy for HTLV-ATLL is conducted through the ETCTN, and correlative studies performed in the current project to assess whether efficacy of lenalidomide is mediated through effects on IRF4, and depend on mutations in TCR pathway components. HTLV load, expression, and clonality assays will be used to monitor the efficacy of therapy. Aim 3: Role of PKCβ activation in ATLL will be examined as an alternative therapeutic target, based on sensitivity of ATLL cells to inhibitors, enzastaurin and midostaurin. We will assess whether sensitivity to these inhibitors are affected by mutations in PKCβ or CARD11, which often co-occur in ATLL. This study will provide in-depth knowledge of the role of TCR signaling in ATLL, and new therapeutic targets.