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 对皮肤T细胞淋巴瘤的病理生理学缺乏明确的认识 （CTCL），特别是其侵袭性白血病形式Sézary综合征，阻碍了 治疗进展，而目前的治疗方法只是治标不治本。虽然CTCL是一个相对 罕见疾病，莫菲特癌症中心恶性血液病和USF皮肤科 每年管理约100名新的CTCL患者。这项研究表明， 由莫菲特的临床研究人员和翻译免疫学家组成的团队， 根据对CTCL患者侵袭性疾病的关键发现， Sézary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，特异性AT富集区结合蛋白1（SATB 1）， 基因组组织者和T细胞发育和成熟的关键调节因子，阻止成熟的T细胞 通过抑制Sézary细胞的关键致病驱动因素来抑制细胞增殖。我们的中央 假设SATB 1通过抑制STAT 5活化， 趋化因子受体控制T细胞归巢到皮肤和转录因子通常 在恶性T细胞中失调。因此，通过靶向组蛋白来恢复SATB 1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解剖 Sézary综合征发病机制的表观遗传机制， 我们的目标是随后通过在我们的诊所更有效的干预措施来针对他们。 在目标1中，我们将阐明SATB 1沉默如何驱动CTCL的发病机制。基于 根据我们的初步结果，我们的假设是Satb 1沉默与Notch信号传导合作， 引发STAT 5-、CCR 10-、IKZF 2/HELIOS依赖性转录程序，导致 胸腺后CD 4 T细胞的进行性扩增、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SATB 1位点。我们将测试SATB 1在以下情况下沉默的假设： Sézary细胞通过K27和K9的组蛋白甲基化的组合，沿着和 赖氨酸去乙酰化，导致染色质可及性的显著变化。 在目标3中，我们将利用我们新的生物学理解来确定以下组合： 更有效地恢复SATB 1表达并阻断致癌信号的表观遗传药物 塞扎里监狱 我们的工作将发挥深远的影响，在该领域阐明如何表观遗传抑制的 主基因组组织者SATB 1控制成熟CD 4 T细胞的恶性转化， 细胞与NOTCH信号协调，导致淋巴细胞在皮肤中的致命积累。 塞扎里的病人这种机制的见解将告知最有效的药物组合 需要去抑制SATB 1位点并拮抗致癌信号，这将推翻 恶性Sézary细胞这一生物学理解将随后进行临床干预， Moffitt用于侵袭性CTCL患者，包括Sézary综合征。