Investigating apoptotic priming as a determinant of sensitivity to leukemia-directed therapies

项目摘要/摘要 急性髓系白血病(AML)是一种致命性血癌，其特征是前体血液克隆性扩张- 形成细胞。几十年来，强化化疗一直是AML治疗的主流。不幸的是，并不是全部 患者身体状况良好，可以接受治疗，尽管进行了密集的治疗，但由于复发而死亡的情况很常见。最近， FDA批准了一种低强度的方案，将去甲基化药物，如氮杂胞苷(Aza)与 Bcl2抑制剂venotclax(VEN)，基于3期随机数据显示总体生存益处和 AML预后亚型的高应答率。Aza/VEN的成功凸显了细胞凋亡途径 作为一个令人兴奋的治疗靶点。文奈德通过拮抗血管紧张素转换酶的抗细胞凋亡作用诱导细胞凋亡 BCL2，许多线粒体BH3结构域蛋白之一，调节AML原始细胞死亡的阈值。 在存活的白血病母细胞中，这种凋亡阈值或启动可以通过功能细胞死亡分析来测量， 被称为BH3剖析。我最近证明了白血病转化的起源细胞会影响 通过P53活性的改变启动细胞凋亡和由此产生的治疗敏感性。我感兴趣的是 了解AML细胞状态，无论是由AML基因建立的，还是由细胞凋亡引发的，都可以影响 在p53功能减弱的背景下的药物敏感性和临床结果。我假设BH3的侧写 AML患者样本的比例可作为预测Aza/VEN治疗反应的生物标志物。我还假设 突变的TP53引起的复杂的细胞遗传学变化促进了AML的发生 Aza/VEN的进展和治疗耐药性与突变体TP53无关。我相信这项工作将会 解决具有治疗意义的重要生物学问题： 1.在异种移植小鼠模型中，BH3谱分析能否预测对Aza/VEN的治疗反应？ 2.在AML细胞中，哪些转录和表观遗传途径参与了低凋亡的启动和 对Aza/VEN反应迟钝？ 3.TP53功能丧失背景下的复杂核型AML是旁观者现象还是旁观者现象 增强白血病致瘤性和/或对Aza/VEN和化疗等治疗的抵抗力？ MSKCC的助理主治医生蔡胜博士将进行这项研究，作为其职业发展计划的一部分。 把85%的时间都用在研究上。蔡医生的导师是世界血液学专家罗斯·莱文博士 恶性肿瘤。他的顾问还包括Anthony Letai博士(他开发了BH3剖析分析)，Scott Lowe， 迈克尔·哈拉斯、理查德·科赫和安德烈·德尔卡奇。蔡博士的培训将包括在 生物标志物验证和生物信息学和遗传小鼠模型方面的专业知识，长期目标是 作为血液病恶性疾病发展的独立调查者制定研究计划 用于精确肿瘤学的功能化生物标记物分析。

PROJECT SUMMARY/ABSTRACT Acute myeloid leukemia (AML) is a lethal blood cancer characterized by a clonal expansion of precursor blood- forming cells. Intensive chemotherapy has been the mainstay of AML therapy for decades. Unfortunately, not all patients are fit enough to receive it and mortality due to relapse despite intensive treatment is common. Recently, the FDA approved a lower intensity regimen combining a hypomethylating agent, such as azacitidine (aza), with the BCL2 inhibitor venetoclax (ven), based on phase 3 randomized data showing an overall survival benefit and high response rates across AML prognostic subtypes. The success of aza/ven highlights the apoptotic pathway as an exciting therapeutic target. Venetoclax induces apoptosis by antagonizing the anti-apoptotic function of BCL2, one of many mitochondrial BH3-domain proteins that regulate the threshold at which an AML blast dies. This apoptotic threshold, or priming, in viable leukemic blasts can be measured via a functional cell death assay, called BH3 profiling. I have recently demonstrated that the cell of origin of leukemic transformation influences apoptotic priming and resultant therapeutic sensitivity via alterations in p53 activity. I am interested in understanding how AML cell state, whether established by AML genotype or apoptotic priming, can influence drug sensitivity and clinical outcomes in the context of attenuated p53 function. I hypothesize that BH3 profiling of AML patient samples can serve as a biomarker to predict treatment response to aza/ven. I also hypothesize that complex cytogenetic changes – ensuing from mutant TP53-induced genomic instability – promote AML progression and therapeutic resistance to aza/ven independent of mutant TP53. I believe that this work will address important biological questions with therapeutic implications: 1. Can BH3 profiling assays predict treatment response to aza/ven in xenograft mouse models? 2. Which transcriptional and epigenetic pathways are engaged in AML cells with low apoptotic priming and blunted responsiveness to aza/ven? 3. Is complex karyotype AML in the setting of TP53 loss of function a bystander phenomenon, or does it enhance leukemogenicity and/or resistance to therapies such as aza/ven and chemotherapy? Dr. Sheng Cai, an Assistant Attending at MSKCC, will conduct this study as part of his career development plan, dedicating 85% of his time to research. Dr. Cai is mentored by Dr. Ross Levine, a world expert in hematologic malignancies. He is also advised by Drs. Anthony Letai (who developed the BH3 profiling assay), Scott Lowe, Michael Kharas, Richard Koche, and Andriy Derkach. Dr. Cai's training will include gaining knowledge in biomarker validation and expertise in bioinformatics and genetic mouse models, with the long term goal of developing a research program as an independent investigator in hematologic malignancies developing functionalized biomarker assays for precision oncology.