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

• 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
• 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

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.

摘要