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Interrogating oncogene-dependency and mutation order in FLT3 mutant AML

探究 FLT3 突变 AML 中的癌基因依赖性和突变顺序

基本信息

批准号：
10669825
负责人：
Robert Lyle Bowman
金额：
$ 24.9万
依托单位：
UNIVERSITY OF PENNSYLVANIA
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：
2022-09-01 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10669825
关键词：
Ablation Acute Myelocytic Leukemia Address Affect Alleles Automobile Driving CRISPR/Cas technology Cells Clinical Clinical Trials Clonal Evolution Coculture Techniques Communication DNA Sequence Alteration DNMT3a Dependence Development Disease Disease Progression Doctor of Philosophy Epigenetic Process Event FDA approved FLP recombinase FLT3 gene FLT3 inhibition FLT3 inhibitor Foundations Future Gene Frequency Genes Genetic Genetic Transcription Genomics Goals Grant Head Hematologic Neoplasms Heterogeneity Human In complete remission Intervention Laboratories Lead Lesion Leukemic Cell Link Maintenance Malignant - descriptor Malignant Neoplasms Memorial Sloan-Kettering Cancer Center Mentors Methods Minor Modeling Molecular Mutate Mutation Myeloid Leukemia NPM1 gene Oncogene Activation Oncogenes Oncogenic Oncology Outcome Pathogenesis Patients Pharmaceutical Preparations Phase Postdoctoral Fellow Predisposition Process Prognostic Marker Protein Tyrosine Kinase Receptor Protein-Tyrosine Kinases Relapse Reporter Research Research Institute Resistance Resources Role Signal Transduction Site Somatic Mutation System Technical Expertise Testing Therapeutic Treatment Efficacy anticancer research career career development chemical genetics clinically relevant efficacious treatment epigenetic drug epigenome fitness genetic epidemiology genetic variant improved in vivo inhibitor insight leukemia leukemic transformation leukemogenesis member mouse model mutant novel novel therapeutics programs recombinase relapse patients research and development response skills small molecule success therapeutic target tool tool development treatment response tumor microenvironment

项目摘要

PROJECT ABSTRACT/SUMMARY CANDIDATE: I am a postdoctoral fellow in the laboratory of Dr. Ross Levine in the Human Oncology and Pathogenesis Program at Memorial Sloan Kettering Cancer Center. My previous PhD research offered me the opportunity to develop the experimental and computational skills necessary to assess cellular crosstalk in the tumor microenvironment. My current research extends these skills to the study of mutation order, and oncogene-dependency in subpopulations of leukemic cells. To gain insights into these processes I developed novel, multi-recombinase mouse models of oncogene-activation and dependency as well as new lineage tracing tools that allow for functional interrogation of clonal evolution. My proposed research will provide a strong foundation for independent research following the K99 phase of this grant. My long-term career goal is to identify molecular mechanisms driving leukemogenesis, including interactions between AML subclones in vivo and the role of sequential mutational acquisition. To achieve these goals I have developed a career plan that will 1) bolster my technical skills and scientific scope, 2) improve my presentation and communication skills, 3) cultivate professional relationships and networking, and 4) prepare me for mentoring future trainees. RESEARCH: The receptor tyrosine kinase, FLT3, is the most commonly mutated gene in acute myeloid leukemia. Mutations in FLT3 are often found with low variant allele frequency, suggesting these mutations occur as late, subclonal events. Despite their presence as a minor clone, FLT3 mutations are poor prognostic markers and the target of several recently approved clinical compounds. These inhibitors lead to some transient clinical success, yet patients invariably relapse and develop resistant, calling into question the necessity of FLT3 mutation in disease progression. I aim to determine the dependency of FLT3 mutations in disease, and propose methods to assess the functional contributions of subclonal mutations to disease progression. The specific aims are: 1) determining the genomic context for FLT3 oncogene-dependency in AML, 2) identifying novel therapeutic vulnerabilities in FLT3-driven AML, and 3) investigating the role of mutation order and clonal crosstalk in leukemic disease. ENVIRONMENT: The Levine laboratory is a part of the Human Oncology and Pathogenesis Program (HOPP) at Memorial Sloan Kettering Cancer Center, a state of the art cancer research institute. The Levine lab is also a member of the Center for Epigenetic Research, and the primary mentor Dr. Levine, is the head of the Center for Hematologic Malignancies. These affiliations provide a rich set of collaborative, technical and scientific resources to execute the research and career development proposed here.

项目摘要/总结