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

项目概要/摘要 急性髓性白血病（AML）是一种致命的血液癌症，其特征是前体血液细胞的克隆扩增， 形成细胞。几十年来，强化化疗一直是AML治疗的支柱。但并不是所有 病人的健康状况足以接受治疗，尽管进行了密集治疗，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治疗方案，将低甲基化剂如阿扎胞苷（aza）与 BCL 2抑制剂venetoclax（ven），基于3期随机数据显示总生存期获益， AML预后亚型的缓解率更高。aza/ven的成功突出了凋亡途径 作为一个令人兴奋的治疗目标。维奈托克通过拮抗抗凋亡作用诱导细胞凋亡 BCL 2，一种调节AML原始细胞死亡阈值的线粒体BH 3结构域蛋白。 在活的白血病母细胞中的这种凋亡阈值或引发可以通过功能性细胞死亡测定来测量， 称为BH 3分析。我最近证明了白血病转化的起源细胞影响 通过p53活性的改变引起细胞凋亡和产生的治疗敏感性。我感兴趣 了解AML细胞状态如何，无论是由AML基因型还是凋亡引发建立， p53功能减弱背景下的药物敏感性和临床结局。我假设BH 3基因分析 的AML患者样本可以作为生物标志物来预测对aza/ven的治疗反应。我还假设 复杂的细胞遗传学变化--由突变型TP 53诱导的基因组不稳定性引起--促进AML 不依赖于突变体TP 53的对aza/ven的进展和治疗抗性。我相信这项工作将 解决具有治疗意义的重要生物学问题： 1. BH 3谱分析法能否预测异种移植小鼠模型对aza/ven的治疗反应？ 2.哪些转录和表观遗传途径参与了低凋亡启动的AML细胞， 对aza/ven的反应迟钝？ 3.在TP 53功能丧失的背景下，复杂核型AML是一种旁观者现象，还是 增强致白血病性和/或对诸如aza/ven和化疗的疗法的抗性？ 博士蔡胜，MSKCC的助理主治医师，将进行这项研究作为他职业发展计划的一部分， 他把85%的时间用于研究蔡博士由世界血液学专家Ross Levine博士指导 恶性肿瘤他还得到了Anthony Letai博士（他开发了BH 3分析测定法），Scott Lowe博士， Michael Kharas Richard Koche和Andriy Derkach。蔡博士的培训将包括获得知识， 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 作为一名独立的血液恶性肿瘤研究者， 用于精确肿瘤学的功能化生物标志物测定。

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.