Unlocking the Therapeutic Potential of Retinoic Acid in Acute Myeloid Leukemia

释放视黄酸在急性髓系白血病中的治疗潜力

基本信息

批准号：
9179459
负责人：
Ronan Thomas Swords
金额：
$ 20.03万
依托单位：
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-01 至 2018-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9179459
关键词：
Accounting Acute Acute Myelocytic Leukemia Acute Promyelocytic Leukemia Affect Aftercare Apoptosis Area Blast Cell Blood Bone Marrow Cell Culture Techniques Cell Line Cells Chromosomal translocation Clinic Clinical Complex Country Critiques Data Development Diagnosis Differentiation Antigens Disease Disease remission Dysmyelopoietic Syndromes Engraftment FDA approved Flow Cytometry Genes Goals Growth HL-60 Cells Hematopoietic stem cells Histone H3 Human ITGAM gene Incidence Knowledge Laboratories Lesion Licensing Lysine Malignant Neoplasms Medicine Methyltransferase Mono-S Monoamine Oxidase Monoamine Oxidase Inhibitors Mononuclear Mus Myelogenous Myeloid Leukemia Nature New Drug Approvals Parnate Pathogenesis Patients Pharmaceutical Preparations Play Population Positioning Attribute Publications Publishing Regulation Reporting Resistance Retinoids Role Safety Sampling Seminal Sequence Homology Testing Therapeutic Transplantation Tranylcypromine Tretinoin Work abstracting base cell growth design disorder subtype effective therapy exhaustion histone methylation improved in vivo inhibitor/antagonist leukemia leukemic stem cell mouse model novel therapeutic intervention novel therapeutics overexpression phase I trial programs promoter research study resistance mechanism restoration retinoic acid receptor alpha success therapeutic target time use transcription factor translational study treatment response

项目摘要

Abstract My principal area of focus is in the design of new therapeutic strategies for patients with acute myeloid leukemia (AML) and myelodysplasia, which are fatal diseases for the majority of patients. The retinoid all-trans-retinoic acid (ATRA) is highly effective therapy for acute pro-myelocytic leukemia (APL), with 70% of patients achieving remission when treated with ATRA alone. Several attempts have been made to re-produce the efficacy of ATRA in non-APL AML but none have been successful. Malfunction of the ATRA regulated transcription factor RARA (retinoic acid receptor alpha), is likely to play an important role in the pathogenesis of non-APL AML. It has been widely reported that RARA function is blocked in these leukemias by mechanisms other than through chromosomal translocation (which characterizes the driver lesion in APL). Defining and understanding these alternative lesions may help in extending the role of ATRA beyond APL. Data published from our lab in Nature Medicine has shown that the RARA promoter is suppressed due to the loss of activating histone methylation marks. Additional experiments in non-APL cell lines confirmed over-expression of the de-methylase LSD1, which blocks RARA promoter function by directly de-methylating di- and mono-methyl lysine 4 on histone H3. Importantly, LSD1 can be inhibited by monoamine oxidase inhibitors (MAOIs) because of sequence homology between LSD1 and cellular monoamine oxidases. By overcoming LSD1 negative regulation, non-APL cells are re-sensitized to ATRA induced differentiation. The combination of TCP (an approved MAOI, Parnate, GSK) potently synergizes with ATRA in non-APL AML to induce differentiation, post differentiation apoptosis and exhaustion of the leukemic stem cell pool (see figure below), without adversely affecting normal hematopoietic stem cells (HSC). Based on these published data, the studies proposed in this project will test the combination of TCP with ATRA for leukemia patients to extend the success of ATRA into other forms of AML.

抽象的我的主要关注领域是为急性髓系白血病患者设计新的治疗策略（AML）和骨髓增生异常，这对大多数患者来说是致命的疾病。类视黄醇全反式视黄酸酸（ATRA）是治疗急性早幼粒细胞白血病（APL）的高效疗法，70%的患者达到了治疗效果单独使用 ATRA 治疗可缓解。为了再现 ATRA 的功效，已经进行了多次尝试在非 APL AML 中，但没有一个取得成功。 ATRA 调节转录因子 RARA 发生故障（视黄酸受体α）可能在非APL AML 的发病机制中发挥重要作用。它一直据广泛报道，RARA 功能在这些白血病中被其他机制阻断染色体易位（APL 中驱动病变的特征）。定义和理解这些替代性病变可能有助于将 ATRA 的作用扩展到 APL 之外。我们实验室在《自然》杂志上发表的数据医学表明，RARA启动子因失去激活组蛋白甲基化而受到抑制标记。在非 APL 细胞系中进行的其他实验证实了去甲基化酶 LSD1 的过度表达，通过直接去甲基化组蛋白 H3 上的二甲基和单甲基赖氨酸 4 来阻断 RARA 启动子功能。重要的是，由于序列同源性，LSD1 可以被单胺氧化酶抑制剂 (MAOIs) 抑制 LSD1 和细胞单胺氧化酶之间的关系。通过克服 LSD1 负调控，非 APL 细胞对 ATRA 诱导的分化重新敏感。 TCP的组合（已批准的MAOI、Parnate、GSK）在非 APL AML 中与 ATRA 有效协同作用，诱导分化、分化后细胞凋亡和白血病干细胞库耗尽（见下图），而不会对正常造血产生不利影响干细胞（HSC）。根据这些已发表的数据，本项目中提出的研究将测试该组合 TCP 联合 ATRA 治疗白血病患者，将 ATRA 的成功扩展到其他形式的 AML。