Unlocking the Therapeutic Potential of Retinoic Acid in Acute Myeloid Leukemia

摘要 我的主要研究领域是为急性髓系白血病患者设计新的治疗策略 急性髓系白血病(AML)和骨髓发育不良，对大多数患者来说都是致命的疾病。维甲酸全反式维甲酸 酸性(ATRA)是治疗急性早幼粒细胞白血病(APL)的高效药物，70%的患者达到 单独使用全反式维甲酸治疗时缓解。人们曾多次尝试重现全反式维甲酸的疗效 在非急性早幼粒细胞白血病中，但没有一例成功。全反式维甲酸调控的转录因子RARA功能障碍 (视黄酸受体α)，可能在非APL AML的发病机制中发挥重要作用。一直以来 广泛报道，在这些白血病中，Rara功能被阻断的机制不是通过 染色体易位(这是APL的驱动损害的特征)。定义和理解这些 替代病变可能有助于将全反式维甲酸的作用扩展到APL之外。我们在《自然》杂志上的实验室公布的数据 医学研究表明，由于失去了激活组蛋白甲基化，RARA启动子受到抑制 马克。在非APL细胞系中的其他实验证实了脱甲基酶LSD1的过度表达，该酶 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启动子的功能。 重要的是，由于序列的同源性，LSD1可以被单胺氧化酶抑制剂(MAOIs)抑制 在LSD1和细胞单胺氧化酶之间。通过克服LSD1负调控，非APL细胞 对全反式维甲酸再敏化诱导分化。TCP(经批准的MAOI、PARATE、GSK)的组合 在非APL AML中有效地与ATRA协同诱导分化、分化后凋亡和 耗尽白血病干细胞库(见下图)，不会对正常造血造成不利影响 干细胞(HSC)。基于这些公布的数据，本项目中提出的研究将测试这一组合 Tcp联合ATRA在白血病患者中的应用，将ATRA的成功扩展到其他形式的AML。

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.