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A rapid spontaneous murine model of CN-AML

CN-AML 快速自发小鼠模型

基本信息

批准号：
9174448
负责人：
H. LEIGHTON GRIMES
金额：
$ 62.54万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-01 至 2019-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9174448
关键词：
Acute Myelocytic Leukemia Address Adult Algorithms Alleles Animal Model Architecture Bioinformatics Biological Biological Markers Biological Response Modifier Therapy Bone Marrow Catalytic Domain Cells Chemotherapy-Oncologic Procedure Chromosomal translocation Classification Complex Cytogenetics DNA Modification Methylases DNMT3a Data Data Set Disease Epidemiologic Studies Event Exons FLT3 gene FLT3 inhibitor Frequencies Gene Expression Gene Targeting Genes Genetic Markers Genetically Engineered Mouse Genomics Hematopoietic Hematopoietic stem cells Heterogeneity Human Ligands MLL-AF9 Malignant Neoplasms Metamyelocyte Modeling Molecular Molecular Target Mouse Strains Mus Mutation Myeloproliferative disease Oncogenes Oncogenic Outcome Pathogenesis Patients Pattern Penetrance Population Proteins Receptor Protein-Tyrosine Kinases Relapse Research Residual Neoplasm Resistance Risk Sampling Signal Transduction Somatic Mutation Spectral Karyotyping Stat5 protein Testing Therapeutic Validation Work bisulfite sequencing c-myc Genes chemotherapy clinically relevant disorder risk exome sequencing fetal liver kinase-2 genome sequencing in vivo leukemia methylome molecular pathology mouse model mutant novel novel therapeutic intervention outcome forecast programs response standard of care targeted treatment transcriptome transcriptome sequencing treatment response tumor whole genome

项目摘要

ABSTRACT Acute myeloid leukemia (AML) is genetically complex, but patients can be divided into those with chromosomal translocations and those that are cytogenetically normal (CN-AML). CN-AML represents nearly 50% of human AML cases, and the overall 5-year survival for adults with CN-AML is approximately 30%. Mutations in the de novo DNA methyltransferase DNMT3A and internal tandem duplications of the FMS-like tyrosine kinase 3 (FLT3-ITD) and are two of the most frequent events in CN-AML. Moreover, recent whole-genome sequencing of CN-AML patient samples identified: 1) high-frequency co-occurrence of FLT3 and DNMT3A mutations, and 2) corresponding changes to the risk classification for these CN-AML patients to a poorer prognosis. Because human epidemiologic studies cannot easily control for factors that confer disease risk, genetically engineered mouse (GEM) strains provide essential tractable platforms to mechanistically dissect disease pathobiology, heterogeneity and therapeutic response. Although neither Flt3-ITD nor inducible deletion of Dnmt3a induces spontaneous leukemia in mice, when we combined Flt3-ITD mutant alleles with inducible deletion of Dnmt3a we find a spontaneous, rapidly lethal, completely-penetrant, and transplantable AML. We hypothesize that inducible deletion of Dnmt3a in Flt3-ITD mice produces a faithful model of human CN-AML that can be used to infer essential biological and molecular factors that constitute therapeutic response. To this end, we propose, genomic, cytogenetic, and single-cell molecular analyses (with comparison to primary human CN-AML) to deconvolute both the tumor architecture and the underlying cellular states. We expect the proposed research to deliver a validated murine model of FLT3-ITD/DNMT3a-mutant CN-AML with defined translational utility.

摘要