Targetable epigenetic mechanism driving Cutaneous T cell Lymphoma

驱动皮肤T细胞淋巴瘤的靶向表观遗传机制

• 批准号: 10800864
• 负责人: Jose R Conejo-Garcia
• 金额: $ 38.8万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-02 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10800864
• 关键词: AT Rich Sequence; Ablation; American Cancer Society; Automobile Driving; Binding Proteins; Biological; Blood; CD4 Positive T Lymphocytes; Cancer Center; Chromatin; Clinic; Clinical; Clinical Investigator; Collection; Cutaneous T-cell lymphoma; Deacetylation; Deletion Mutation; Dermatology; Diagnosis; Disease; Down-Regulation; Drug Combinations; Epigenetic Process; Etiology; Functional disorder; GPR2 gene; Genetic Transcription; Genomics; Goals; Growth and Development function; Hematologist; Hematology; Histone Deacetylase; Histone Deacetylation; Homing; Human; Immunologist; Intervention; Lymphocyte; Lymphoma cell; Lysine; Malignant - descriptor; Mature T-Lymphocyte; Methyltransferase; Molecular; Oncogenic; Organ; Outcome; Pathogenesis; Pathogenicity; Patients; Peripheral; Phosphorylation; Point Mutation; Rare Diseases; Repression; Role; Sampling; Scheme; Sezary Syndrome; Sezary cell; Signal Transduction; Skin; Small-Cell Lymphoma; Specimen; Stat5 protein; Survival Rate; T-Cell Development; T-Cell Lymphoma; T-Lymphocyte; Testing; Therapeutic; Thymus Gland; Tumor Suppressor Proteins; Work; chemokine receptor; clinical translation; cytokine; derepression; design; effective intervention; effective therapy; epigenetic drug; epigenetic silencing; histone methylation; inhibitor; insight; leukemia; lymph nodes; malignant phenotype; mouse model; notch protein; novel; overexpression; palliative; prevent; programs; promoter; transcription factor

ABSTRACT The lack of a clear understanding of the pathophysiology of Cutaneous T cell Lymphoma (CTCL) and in particular its aggressive leukemic form Sézary Syndrome, has impeded therapeutic advances, and current treatments are only palliative. Although CTCL is a relatively rare disease, Moffitt Cancer Center Malignant Hematology and USF Dermatology Departments manages about 100 new patients with CTCL annually. This study represents a concerted effort by a team of clinical investigators and translational immunologists at Moffitt to identify new effective treatments for CTCL patients with aggressive disease, based on the discovery of key molecular regulators of Sézary Syndrome development and growth. Specifically, our new mouse models indicate that Special AT-rich region binding protein 1 (SATB1), a master genomic organizer and a key regulator of T-cell development and maturation, prevents mature T cell malignization by repressing crucial pathogenic drivers of Sézary cells. Our central hypothesis is that SATB1 acts as a tumor suppressor in CTCL, by repressing STAT5 activation, chemokine receptors that govern T cell homing to the skin and transcription factors commonly de-regulated in malignant T cells. Accordingly, restoring SATB1 expression by targeting histone methylation and de-acetylation will avert the malignant phenotype of Sézary cells. We will leverage a growing collection of aphaeresis specimens and unique mouse models to dissect the epigenetic mechanisms governing the pathogenesis of Sézary Syndrome, with the overarching goal of subsequently targeting them through more effective interventions in our clinic. In Aim 1, we will elucidate how SATB1 silencing drives the pathogenesis of CTCL. Based on our preliminary results, our hypothesis is that Satb1 silencing cooperates with Notch signaling to elicit a STAT5-, CCR10-, IKZF2/HELIOS-dependent transcriptional program leading to the progressive expansion, skin homing and malignant transformation of post-thymic CD4 T cells. In Aim 2, we will define the complementary mechanisms leading to epigenetic silencing of the SATB1 locus in Sézary Syndrome. We will test the hypothesis that SATB1 is silenced in Sézary cells through a combination of histone methylation at K27 and K9 that, along with and lysine de-acetylation, resulting in significant changes in chromatin accessibility. In Aim 3, we will leverage our new biological understanding to identify the combination of epigenetic drugs that more effectively restore SATB1 expression and thwart oncogenic signals in Sézary cells. Our work will exert a profound effect in the field by elucidating how epigenetic repression of the master genomic organizer SATB1 governs the malignant transformation of mature CD4 T cells in coordination with NOTCH signaling, leading to fatal skin accumulation of lymphocytes in Sézary patients. This mechanistic insight will inform the most effective combination of drugs needed to de-repress the SATB1 locus and antagonize oncogenic signals, which will overturn malignant Sézary cells. This biological understanding will be followed by clinical interventions at Moffitt for patients with aggressive CTCL, including Sézary Syndrome.

摘要 皮肤T细胞淋巴瘤的病理生理学缺乏明确认识 (CTCL)，特别是其侵袭性白血病形式S-扎里综合征，阻碍了 治疗方面的进展，目前的治疗只是姑息性的。虽然CTCL是一种相对 罕见疾病，莫菲特癌症中心恶性血液科和USF皮肤科 每年管理约100名新的CTCL患者。这项研究代表了一项共同的努力 由莫菲特的临床研究人员和转化免疫学家组成的团队发现了新的 CTCL患者侵袭性疾病的有效治疗，基于关键的发现 S综合征发生和生长的分子调节因子。具体地说，我们的新 小鼠模型表明，特异的AT富含区域结合蛋白1(SATB1)是一种 基因组组织者和T细胞发育和成熟的关键调节因子，阻止成熟T细胞 通过抑制S细胞的关键致病驱动因素使细胞恶变。我们的中央 假设SATB1在CTCL中作为肿瘤抑制因子，通过抑制STAT5的激活， 控制T细胞归巢到皮肤的趋化因子受体和通常的转录因子 在恶性T细胞中去调节。因此，通过靶向组蛋白来恢复SATB1的表达 甲基化和去乙酰化将避免S细胞的恶性表型。我们会 利用越来越多的失语症标本和独特的小鼠模型来解剖 S综合征发病的表观遗传学机制 目标是随后在我们的诊所通过更有效的干预来针对他们。 在目标1中，我们将阐明SATB1沉默如何在CTCL的发病机制中起作用。基于 我们的初步结果是，我们的假设是Satb1沉默与Notch信号协同作用 诱导依赖STAT5、CCR10、IKZF2/HELIOS的转录程序导致 胸腺后CD4T细胞的渐进性扩张、皮肤归巢和恶变。 在目标2中，我们将定义导致表观遗传沉默的补充机制 S-扎里综合征的SATb1基因座我们将测试SATB1被沉默的假设 S通过K27和K9的组蛋白甲基化的组合，以及和 赖氨酸去乙酰化，导致染色质可及性发生显著变化。 在目标3中，我们将利用我们对生物学的新理解来确定 更有效地恢复SATB1表达和抑制致癌信号的表观遗传药物 在S·扎里的细胞中。 我们的工作将通过阐明表观遗传抑制是如何在该领域产生深远影响的 基因组主组织者SATB1控制成熟的CD4T细胞的恶性转化 细胞与Noch信号协同，导致淋巴细胞在皮肤上致命堆积 S和扎里的病人。这种机械性的洞察力将提供最有效的药物组合 需要去抑制SATB1基因位点并拮抗致癌信号，这将推翻 恶性S细胞。在这种生物学理解之后，将进行临床干预 莫菲特适用于侵袭性CTCL患者，包括S·扎里综合征。