Cohesin Mutations in Core-Binding Factor Acute Myeloid Leukemia

核心结合因子急性髓系白血病的粘连蛋白突变

基本信息

批准号：
10166800
负责人：
Katelyn E Heimbruch
金额：
$ 5.1万
依托单位：
VERSITI WISCONSIN, INC.
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10166800
关键词：
AML1-ETO fusion protein ATAC-seq Acute Myelocytic Leukemia Adult Acute Myeloblastic Leukemia Alleles Animal Model Apoptosis Automobile Driving Basic Science Binding Bone Marrow Cells Bone Marrow Transplantation CBFB gene CBFbeta-MYH11 fusion protein CSPG6 gene Cell Nucleus Cells ChIP-seq Childhood Chimeric Proteins Chromatin Chromosomal Rearrangement Chromosome 16 Chromosome abnormality Chromosomes Clinical Complex Core-Binding Factor DNA DNA Binding Data Dependence Development Disease Engineering Equipment Exhibits Fusion Oncogene Proteins Future Gene Expression Gene set enrichment analysis Genetic Genetic Transcription Genomics Goals Hematopoiesis In Vitro Knowledge Lead Learning Malignant Neoplasms Mentors Molecular Mus Mutation Myelogenous Oncogenes Oncogenic Outcome Pancytopenia Pathway interactions Patients Phenotype Physicians Play Prognosis RUNX1 gene Regulation Relapse Research Resources Role Scientist Signs and Symptoms Testing Toxic effect Training Transplantation Up-Regulation XCL1 gene base cellular transduction chemotherapy cohesin design experimental study genetic makeup genetic signature in vivo individual patient leukemia leukemic transformation leukemogenesis member pressure prognostic self-renewal t(8 21)(q22 q22)targeted treatment therapeutic target transcriptome transcriptome sequencing treatment strategy virtual

项目摘要

Abstract Core-binding factor leukemia represents a subtype of AML and encompasses 30% of pediatric and 15% of adult AMLs. The core-binding factor complex is essential in the regulation of normal hematopoiesis and is composed of AML1 (also known as RUNX1) and CBFB. Chromosomal alterations involving the core-binding factor complex are well-known “drivers” of leukemia development and have similar clinical and prognostic implications. A t(8;21) leads to the fusion oncoprotein AML1-ETO and an inv(16) leads to CBFB-MYH11. Surprisingly, these mutations alone do not induce AML in animal models, suggesting additional “hits” are required. Mutations in one of four members of the cohesin complex (SMC1a, SMC3, RAD21, STAG1) are commonly found in patients with AML and frequently (18-20%) co-occur with AML1-ETO, but never with CBFB-MYH11. This suggests a selective pressure for the presence or absence of cohesin mutations depending upon the driver oncogene. By learning more about the genetic makeup of these leukemias and how additional mutations promote leukemogenesis, we can develop targeted therapies which will reduce both toxicity and the relapse rate compared to existing treatments. We hypothesize that cohesin mutations synergize with AML1-ETO during leukemic transformation, whereas cohesin mutations and CBFB-MYH11 form a synthetic lethal interaction. In Aim 1, in vivo transplant studies will be performed with AML1- ETO;SMC3+/+ compared to AML1-ETO;SMC3+/- while CBFB-MYH11;SMC3+/+ and CBFB-MYH11; SMC3+/- will be studied in vitro. In Aim 2, molecular studies will be performed to delve into the mechanisms driving leukemia. ChIP-sequencing will be performed to identify changes in AML1-ETO genomic occupancy upon introduction of cohesin haploinsufficiency. ATAC-seq and RNA-seq will be performed to identify changes in chromatin accessibility and transcriptome of CBFB-MYH11 due to cohesin haploinsufficiency. Our preliminary studies indicate that the loss of cohesin augments in vitro self-renewal of AML1-ETO transduced cells. Preliminary ATAC-sequencing demonstrates that several motifs implicated in myeloid development (RUNX1, GATA2, ERG, PU.1) are enriched in the AML1-ETO;SMC3+/- background. Further, RNA sequencing reveals upregulation of the MYC, Rb, and E2F oncogenic gene signatures in AML1-ETO;SMC3+/- compared to SMC3+/+. Training potential abounds for a future physician scientist within this proposal as it involves using clinical observations to generate a hypothesis, design a research plan and develop clinical correlations based upon the results of basic science research. Mentoring support will be easily accessible throughout this training, as will be all necessary equipment and resources needed to complete this project.

抽象的核心结合因子白血病是 AML 的一个亚型，涵盖 30% 的儿童和 15% 的成人核心结合因子复合物对于正常造血的调节至关重要，其组成 AML1（也称为 RUNX1）和 CBFB 涉及核心结合因子的染色体改变。复合物是众所周知的白血病发展的“驱动因素”，并且具有相似的临床和预后 t(8;21) 导致融合癌蛋白 AML1-ETO，inv(16) 导致 CBFB-MYH11。令人惊讶的是，这些突变本身并不会在动物模型中诱发 AML，这表明额外的“打击”是粘连蛋白复合物的四个成员（SMC1a、SMC3、RAD21、STAG1）之一发生突变。常见于 AML 患者，并且经常 (18-20%) 与 AML1-ETO 同时发生，但绝不会与 CBFB-MYH11 这表明粘连蛋白突变的存在或不存在存在选择性压力。通过更多地了解这些白血病的基因组成以及如何进行额外的研究。突变促进白血病发生，我们可以开发靶向疗法，既减少毒性又减少副作用与现有治疗相比，我们发现粘连蛋白突变与复发率具有协同作用。白血病转化过程中的 AML1-ETO，而粘连蛋白突变和 CBFB-MYH11 在目标 1 中，将使用 AML1- 进行体内移植研究。 ETO;SMC3+/+ 与 AML1-ETO;SMC3+/- 相比，而 CBFB-MYH11;SMC3+/+ 和 CBFB-MYH11;SMC3+/- 会在目标 2 中，将进行分子研究以深入研究驱动机制。将进行 ChIP 测序以确定 AML1-ETO 基因组占据的变化。将进行粘连蛋白单倍体不足的引入，以识别变化。由于粘连蛋白单倍体不足而导致的 CBFB-MYH11 的染色质可及性和转录组。研究表明，粘连蛋白的丧失增强了 AML1-ETO 转导细胞的体外自我更新。初步 ATAC 测序表明，几个与骨髓发育有关的基序（RUNX1、 GATA2、ERG、PU.1) 在 AML1-ETO 中富集；SMC3+/- 背景此外，RNA 测序显示。与 SMC3+/+ 相比，AML1-ETO;SMC3+/- 中 MYC、Rb 和 E2F 致癌基因特征上调。该提案中未来医师科学家的培训潜力很大，因为它涉及使用临床观察以产生假设、设计研究计划并根据观察结果开发临床相关性在整个培训过程中，将很容易获得基础科学研究的成果。完成该项目所需的所有必要设备和资源。