Clonal dynamics and chemoresistance mechanisms of minimal residual disease in acute leukemia

急性白血病微小残留病的克隆动力学和化疗耐药机制

基本信息

批准号：
10351765
负责人：
Jessie Ann Brown
金额：
$ 13.62万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-02-01 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10351765
关键词：
ATAC-seq Acute Lymphocytic Leukemia Acute Myelocytic Leukemia Acute leukemia Address Adolescent Architecture Automobile Driving CREBBP gene CRISPR screen Cells Cessation of life Chemoresistance Chemotherapy-Oncologic Procedure Child Childhood Childhood Acute Lymphocytic Leukemia Childhood Acute Myeloid Leukemia Childhood Leukemia Chromatin Clinical Clonal Evolution Combination Drug Therapy Complex DNA Sequence Alteration Diagnosis Diagnostic Disease Disease Progression Disease Resistance Disease remission Drug Tolerance Drug resistance Epigenetic Process Event Failure Gene Expression Profile Genes Genetic Genetic Heterogeneity Genetic Transcription Genomics Glucocorticoids Goals Hematologic Neoplasms Heterogeneity Leukemic Cell Link Maintenance Malignant Childhood Neoplasm Malignant Neoplasms Maps Mediating Mentors Metabolic Mission Modernization Molecular Mutation Myeloid Leukemia NR3C1 gene Outcome Pathway interactions Patients Pattern Phase Phenotype Population Progressive Disease Recurrence Recurrent disease Refractory Refractory Disease Relapse Research Proposals Residual Neoplasm Resistance Role Sampling Signal Pathway Signal Transduction Stress TP53 gene Techniques Testing Therapeutic Xenograft procedure advanced analytics analytical tool base chemotherapy disorder prevention epigenomics exome genetic variant high risk improved improved outcome in vivo innovation leukemia leukemia relapse metabolomics multiple omics patient derived xenograft model pediatric acute leukemia programs rational design relapse patients response reverse genetics self-renewal single-cell RNA sequencing targeted treatment therapeutic target therapy design therapy outcome therapy resistant transcriptomics treatment response whole genome

项目摘要

Project Summary. Acute leukemias are aggressive hematological tumors and the most common malignancy in children and adolescents. Though cure rates have steadily improved over the last 50 years with the implementation of intensive chemotherapy regimens, today 20% of pediatric acute lymphoblastic leukemia (ALL) patients will relapse or develop refractory disease. Moreover, therapeutic outcomes in acute myeloid leukemia (AML) are significantly worse with cure rates in the range of 65-70%. Despite much progress in the characterization of the genetic and molecular basis of leukemia, the specific mechanisms mediating resistance, disease progression and relapse remain largely unknown. Thus, genomic profiling analyses have shown marked genetic heterogeneity at relapse which together with the complex combination chemotherapy protocols used in treatment, make it difficult to directly assign precise roles in resistance for most of relapse-associated mutations. My central hypothesis is that genetic mutations, signaling and epigenetic mechanisms controlling self-renewal, response to stress and resistance converge on a restricted number of master regulators that drive the acquisition of a drug-tolerant persistent phenotype at minimal residual disease and ultimately relapse. The objective of this proposal is to establish the specific role of remission- and relapse-associated transcriptional and epigenetic regulators as drivers of drug-tolerant persistent phenotypes and chemotherapy resistance across pediatric acute leukemias. These studies will be impactful to our understanding of the mechanisms conducive to therapeutic failure and will facilitate the rationale design of therapies directed to the eradication of high-risk minimal residual disease and the prevention of leukemia relapse. Towards this goal I propose the following specific aims: Aim 1 (mentored phase): To interrogate by single cell mutational profiling the impact of minimal residual disease composition and clonal dynamics in ALL relapse; Aim 2 (mentored/independent phase): To identify and target master regulators of single cell transcriptional and epigenetic states driving ALL persistence, disease progression and relapse; and Aim 3 (independent phase): To map and target genetic, transcriptional and epigenetic drivers of minimal residual disease and leukemia relapse in pediatric AML. To address these questions, I will use diagnostic-remission-relapse matched leukemia primary samples and leukemia xenografts, combined with single-cell genomics, transcriptomics and epigenomics to functionally characterize convergent mechanisms driving minimal residual disease, resistance and relapse. These analyses will inform functional testing of master regulators and direct single-cell reverse genetic CRISPR screens to define the role of specific genes as drivers of chemoresistance and relapse. These results will ultimately facilitate the rational design of therapies to improve the treatment of this devastating childhood disease.

项目摘要。急性白血病是一种侵袭性血液肿瘤，是儿童和青少年中最常见的恶性肿瘤。青少年。尽管过去 50 年来，随着治疗的实施，治愈率稳步提高。强化化疗方案，如今 20% 的儿童急性淋巴细胞白血病 (ALL) 患者将复发或发展为难治性疾病。此外，急性髓系白血病（AML）的治疗效果治愈率在 65-70% 范围内，情况明显更糟。尽管在表征方面取得了很大进展白血病的遗传和分子基础、介导耐药性的具体机制、疾病进展和复发仍然很大程度上未知。因此，基因组图谱分析显示了显着的遗传复发时的异质性，加上复杂的联合化疗方案治疗，使得很难直接确定大多数与复发相关的突变在耐药性中的精确作用。我的中心假设是基因突变、信号传导和表观遗传机制控制自我更新，对压力和阻力的反应集中在推动收购的有限数量的主监管机构上微小残留病的耐药持续表型并最终复发。此举的目的提议是确定与缓解和复发相关的转录和表观遗传的具体作用监管机构作为儿童急性耐药持久表型和化疗耐药性的驱动因素白血病。这些研究将有助于我们理解有利于治疗的机制失败，并将促进旨在根除高风险微量残留的疗法的合理设计疾病和预防白血病复发。为实现这一目标，我提出以下具体目标：目标 1 （指导阶段）：通过单细胞突变分析来探究微小残留病的影响 ALL 复发时的组成和克隆动态；目标 2（指导/独立阶段）：识别和目标驱动 ALL 持续性和疾病进展的单细胞转录和表观遗传状态的主要调节因子并复发；目标 3（独立阶段）：绘制和定位遗传、转录和表观遗传驱动因素儿童 AML 中微小残留病和白血病复发的影响。为了解决这些问题，我将使用诊断-缓解-复发匹配的白血病原代样本和白血病异种移植物，结合单细胞基因组学、转录组学和表观基因组学在功能上表征收敛机制推动微小残留病、耐药性和复发。这些分析将为 master 的功能测试提供信息调节器和直接单细胞反向遗传 CRISPR 筛选，以确定特定基因作为驱动器的作用化疗耐药和复发。这些结果最终将有助于合理设计治疗方法以改善治疗这种毁灭性的儿童疾病。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Epigenetic reversal of hematopoietic stem cell aging in Phf6-knockout mice.

Phf6 敲除小鼠造血干细胞衰老的表观遗传逆转。

DOI：
发表时间：
2022-11
期刊：
影响因子：
0
作者：
Wendorff, Agnieszka A;Aidan Quinn, S;Alvarez, Silvia;Brown, Jessie A;Biswas, Mayukh;Gunning, Thomas;Palomero, Teresa;Ferrando, Adolfo A
通讯作者：
Ferrando, Adolfo A

m6A RNA modifications: Key regulators of normal and malignant hematopoiesis.

m6A RNA 修饰：正常和恶性造血的关键调节因子。