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: 10204969
• 负责人: Jose R Conejo-Garcia
• 金额: $ 54.85万
• 依托单位: H. LEE MOFFITT CANCER CTR & RES INST
• 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/10204969
• 关键词: AT Rich Sequence; Ablation; Acetylation; 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; 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; Homing; Human; Immunologist; Intervention; Lymphocyte; Lysine; Malignant - descriptor; Mature T-Lymphocyte; Methyltransferase; Molecular; Oncogenic; Organ; Outcome; Pathogenesis; Pathogenicity; Patients; Peripheral; Phosphorylation; 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; base; chemokine receptor; cytokine; design; effective intervention; effective therapy; epigenetic drug; epigenetic silencing; histone methylation; inhibitor/antagonist; 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.

抽象的 对皮肤 T 细胞淋巴瘤的病理生理学缺乏清晰的认识 （CTCL），特别是其侵袭性白血病形式塞扎里综合征，阻碍了 治疗的进展，目前的治疗只是姑息治疗。虽然 CTCL 是相对 罕见病、莫菲特癌症中心恶性血液科和南佛罗里达大学皮肤科 每年管理约 100 名新 CTCL 患者。这项研究代表了共同努力 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 基于关键的发现，对患有侵袭性疾病的 CTCL 患者进行有效的治疗 塞扎里综合征发育和生长的分子调节剂。具体来说，我们的新 小鼠模型表明，特殊 AT 富集区结合蛋白 1 (SATB1) 基因组组织者和 T 细胞发育和成熟的关键调节者，可阻止 T 细胞成熟 通过抑制 Sézary 细胞的关键致病驱动因素来抑制细胞恶性化。我们的中央 假设 SATB1 通过抑制 STAT5 激活在 CTCL 中充当肿瘤抑制因子， 通常控制 T 细胞归巢至皮肤的趋化因子受体和转录因子 恶性 T 细胞中的失调。因此，通过靶向组蛋白恢复 SATB1 表达 甲基化和去乙酰化将避免 Sézary 细胞的恶性表型。我们将 利用越来越多的单采标本和独特的小鼠模型来剖析 控制塞扎里综合征发病机制的表观遗传机制 随后在我们的诊所通过更有效的干预措施来针对他们。 在目标 1 中，我们将阐明 SATB1 沉默如何驱动 CTCL 的发病机制。基于 我们的初步结果，我们的假设是 Satb1 沉默与 Notch 信号协同作用 引发 STAT5-、CCR10-、IKZF2/HELIOS 依赖性转录程序，从而导致 胸腺后 CD4 T 细胞的进行性扩张、皮肤归巢和恶性转化。 在目标 2 中，我们将定义导致表观遗传沉默的互补机制 Sézary 综合征中的 SATB1 基因座。我们将测试 SATB1 在以下情况下被沉默的假设： Sézary 细胞通过 K27 和 K9 处的组蛋白甲基化组合，以及 赖氨酸脱乙酰化，导致染色质可及性发生显着变化。 在目标 3 中，我们将利用新的生物学理解来确定以下组合： 表观遗传药物可以更有效地恢复 SATB1 表达并阻止致癌信号 在塞扎里细胞中。 我们的工作将通过阐明表观遗传抑制如何在该领域发挥深远的影响 主基因组组织者 SATB1 控制成熟 CD4 T 的恶性转化 细胞与 NOTCH 信号传导相协调，导致致命的皮肤淋巴细胞积聚 塞扎里患者。这种机制洞察将指导最有效的药物组合 需要去抑制 SATB1 基因座并拮抗致癌信号，这将推翻 恶性Sézary细胞。这种生物学理解之后将进行临床干预 Moffitt 治疗侵袭性 CTCL 患者，包括塞扎里综合征。