Defining the biological consequences of somatic mutations in high risk AML using integrative single cell approaches

使用综合单细胞方法定义高风险 AML 体细胞突变的生物学后果

• 批准号: 10216162
• 负责人: Maria Sirenko
• 金额: $ 4.6万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-08 至 2022-07-07
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10216162
• 关键词: Acute; Acute Myelocytic Leukemia; Address; Allelic Imbalance; Automobile Driving; Biological; Biology; Blood; Cancer Biology; Cancer Patient; Cells; Chemoresistance; Chemotherapy and/or radiation; Clinical; Clinical Trials; Cytotoxic Chemotherapy; Data; Detection; Development; Diagnosis; Disease; Disease Progression; Early Diagnosis; Early Intervention; Environment; FLT3 gene; Future; Gene Expression; Gene Expression Profile; Gene Expression Profiling; Genes; Genetic; Genome; Genomics; Genotype; Goals; Hematological Disease; Hematopoiesis; Hematopoietic Neoplasms; Individual; Lead; Link; Mediating; Methodology; Methods; Molecular; Mutate; Mutation; Myelogenous; Myeloproliferative disease; Outcome; Pathogenesis; Pathway interactions; Patient-Focused Outcomes; Patients; Phylogenetic Analysis; Principal Investigator; RNA Splicing; Recurrence; Refractory; Relapse; Resistance; Resolution; Risk; Role; SRSF2 gene; Sampling; Schools; Signal Transduction; Solid Neoplasm; Somatic Mutation; Spliced Genes; TP53 gene; Testing; Therapeutic; Time; Training; cancer genomics; cancer initiation; chemotherapy; clinical care; clinically relevant; driver mutation; frontier; high risk; inhibitor/antagonist; insight; leukemic transformation; mutant; novel; patient subsets; personalized medicine; population based; precision medicine; pressure; resistance mechanism; response; risk stratification; single cell sequencing; targeted treatment; therapy resistant; treatment response

Project Summary Acute Myeloid Leukemia (AML) is an aggressive blood cancer with exceedingly poor patient outcomes. Systematic sequencing studies in myeloid neoplasms have identified the recurrent mutations in AML, raising opportunities for the development of targeted therapeutics (e.g. IDH1/2 and FLT3) and molecularly guided clinical care (diagnosis, risk stratification). Despite these recent advances, how these mutations specifically drive pathogenesis and disease progression and define treatment responses is less well understood. Definition of these relationships has been challenged by the genetic and clonal diversity of AML genomes. This proposal aims to study the biological and clinical role of acquired mutations in two complementary contexts: 1) IDH1/2 mutant AML at diagnosis and under IDH inhibitor therapy (targeted therapeutics); 2) TP53 mutant clonal hematopoiesis transformation to AML under cytotoxic therapy for solid tumors (early detection and intervention). To address this question, we established a method to derive single cell genotype and gene expression. We show we can assign single cells to subclones and deliver subclone-specific gene expression profiles in AML. Targeted inhibitors for IDH1 and IDH2 mutations recently attained FDA approval in relapsed/refractory AML, however response remains highly variable. In these clinical trials, patients with subclonal mutations in signaling or splicing genes were more likely to be non-responders. The first specific aim is to define the role of acquired mutations in IDH1/2-mutant AML at diagnosis and under IDH inhibitor therapy using integrative single cell approaches. We hypothesize that the biological effectors of signaling and splicing mutations drive subclonal gene expression profiles mediating resistance, distinct from the inhibitor-sensitive dominant clone. Our preliminary data identifies mutations in TP53 at clonal hematopoiesis are associated with subsequent acquisition of allelic imbalances and transformation to AML under chemotherapy for solid tumors. The second specific aim is to study mechanisms of TP53 mutant clonal hematopoiesis transformation to therapy-related myeloid neoplasm using integrative single cell approaches. We will test the hypothesis that TP53 mutations provide fertile ground for allelic imbalances and these aberrations together drive progression to AML. Together, these aims inform how individual mutations contribute to myeloid pathogenesis during disease initiation, progression, and under the selective pressure of treatment. This will provide insight into AML disease biology, clinical response, and the development of new early detection and therapeutic strategies. Dr. Elli Papaemmanuil and Dr. Ross Levine, with expertise in the functional and clinical consequences of somatic mutations in myeloid malignancies, serve as Sponsors of this application. The Gerstner Sloan Kettering Graduate School provides the optimal training environment for the applicant. This training will advance the applicant’s goal to become a principal investigator on the frontier of cancer biology and genomics.

项目摘要 急性髓系白血病(AML)是一种侵袭性血癌，患者预后极差。 髓系肿瘤的系统测序研究已经确定了AML的复发突变，提高了 发展靶向疗法(如IDH1/2和Flt3)和分子指导临床的机会 护理(诊断、风险分层)。尽管最近取得了这些进展，但这些突变是如何具体推动 发病机制和疾病进展以及确定治疗反应还不太清楚。定义 这些关系受到了AML基因组的遗传和克隆多样性的挑战。这项提议旨在 在两个互补的背景下研究获得性突变的生物学和临床作用：1)IDH1/2突变 确诊时的AML和IDH抑制剂治疗(靶向治疗)；2)TP53突变克隆性造血 实体瘤细胞毒治疗向AML转化(早期发现和干预)。 为了解决这个问题，我们建立了一种获得单细胞基因型和基因表达的方法。我们 表明我们可以将单个细胞分配给亚克隆，并在AML中提供亚克隆特异性的基因表达谱。 IDH1和IDH2突变的靶向抑制剂最近获得了FDA对复发/难治性AML的批准， 然而，人们的反应仍然很不稳定。在这些临床试验中，信号亚克隆突变的患者 或者剪接基因更有可能是无反应的。第一个具体目标是定义获得者的角色 IDH1/2突变型急性髓细胞白血病在诊断和IDH抑制剂治疗下的突变 接近了。我们假设信号和剪接突变的生物效应器驱动亚克隆 基因表达谱介导抗性，不同于对抑制剂敏感的显性克隆。 我们的初步数据确定克隆造血时TP53的突变与随后的 实体瘤化疗中等位基因失衡的获得和向AML的转化。第二 具体目的是研究TP53突变克隆性造血转化为治疗相关的机制 使用整合的单细胞方法治疗髓系肿瘤。我们将测试TP53突变的假设 为等位基因失衡提供了肥沃的土壤，这些异常共同推动了AML的进展。 这些目的共同揭示了个体突变如何在疾病期间促进髓系疾病的发生。 在选择性治疗的压力下，开始、进展。这将提供对AML疾病的洞察 生物学、临床反应以及新的早期发现和治疗策略的发展。 埃利·帕帕曼纽尔博士和罗斯·莱文博士，在功能和临床后果方面拥有专业知识 髓系恶性肿瘤的体细胞突变是这项应用的发起人。格斯特纳·斯隆·凯特林 研究生院为申请者提供最佳的培训环境。这项培训将推进 申请者的目标是成为癌症生物学和基因组学前沿的首席研究员。

项目成果

Interplay between chromosomal alterations and gene mutations shapes the evolutionary trajectory of clonal hematopoiesis.

• DOI: 10.1038/s41467-020-20565-7
• 发表时间: 2021-01-12
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Gao T;Ptashkin R;Bolton KL;Sirenko M;Fong C;Spitzer B;Menghrajani K;Ossa JEA;Zhou Y;Bernard E;Levine M;Martinez JSM;Zhang Y;Franch-Expósito S;Patel M;Braunstein LZ;Kelly D;Yabe M;Benayed R;Caltabellotta NM;Philip J;Paraiso E;Mantha S;Solit DB;Diaz LA Jr;Berger MF;Klimek V;Levine RL;Zehir A;Devlin SM;Papaemmanuil E
• 通讯作者: Papaemmanuil E