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Characterizing the pathogenesis and targeted therapeutics of Wilms' Tumor 1 (WT1) mutations in AML

描述 AML 中 Wilms 肿瘤 1 (WT1) 突变的发病机制和靶向治疗

基本信息

批准号：
10459634
负责人：
Haijiao Zhang
金额：
$ 24.9万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
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：
2019-04-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10459634
关键词：
Acute Advisory Committees Apoptosis BCL2 gene Bioinformatics Biological Assay Bone Marrow Bone Marrow Cells Bone Marrow Stem Cell C-terminal CEBPA gene CRISPR screen CSF3R gene Candidate Disease Gene Caring Cell Line Cell Lineage Cell Proliferation Cells Chemoresistance Clinic Clustered Regularly Interspaced Short Palindromic Repeats Colony-Forming Units Assay Combined Modality Therapy Cytarabine Cytogenetics Data Development Dimerization Disease Disease Progression Dose Drug resistance Drug usage Engineering Exons FLT3 gene FLT3 inhibitor Faculty Frameshift Mutation Genes Goals Growth Hematologic Neoplasms Hematopoietic stem cells Human Inbred BALB C Mice Leukemic Cell Manuscripts Mediating Medical Medical Students Mentors Mentorship Modality Modeling Molecular Monitor Mus Mutation Myeloid Leukemia N-terminal Oncogenes Oncogenic Outcome Pathogenesis Pathway interactions Patients Pharmaceutical Preparations Phase Phenotype Positioning Attribute Preparation Prognosis Publishing RNA Recurrent disease Refractory Regulatory Element Research Research Personnel Resistance Sampling Series Sum Therapeutic Training Transcriptional Regulation Translations Transplantation Tyrosine Kinase Domain WT1 gene Xenograft procedure Zinc Fingers career chemotherapy clinical predictors clinically relevant combinatorial deep sequencing disease phenotype drug candidate drug sensitivity functional genomics gene therapy genome editing genome-wide in vivo inhibitor leukemia leukemia treatment leukemic stem cell loss of function mouse model mutant myeloid leukemia cell novel therapeutics overexpression progenitor receptor resistance mechanism resistance mutation screening standard care stem cell biology targeted cancer therapy targeted treatment therapeutic target transcription factor transcriptome sequencing translational medicine variant of unknown significance

项目摘要

PROJECT SUMMARY/ABSTRACT Dr. Haijiao Zhang has been training as a medical student for 7 years with a focus on hematological malignancies and as a researcher for 6 years in the field of characterizing oncogene and drug resistance mechanisms. Her research has led to 8 published manuscripts and 4 other manuscripts in submission /preparation. The theme of Dr. Zhang's research involves systematic characterization of leukemia oncogenes and understanding leukemia drug resistance mechanisms. She has characterized 4 distinct mechanisms of CSF3R mutations and diverse mechanisms associated with drug resistance to the FLT3 inhibitor crenolanib. The WT1 (Wilms' tumor 1) gene encodes a transcription factor with C-terminal zinc-finger domains, whereas the N-terminal part contains domains that mediate receptor dimerization, RNA recognition, and transcriptional regulation. WT1 mutations are present in approximately 10–15% of AML and are associated with chemotherapy resistance and disease relapse. WT1 mutations are frameshift mutations or substitutions across all structural domains, predominantly in exons 7 and 9. The pathogenesis mediated by loss-of-function of WT1 zinc finger domain mutations has been studied; however very little is known about the oncogenic potential, drug sensitivity, and the structural basis of mutations residing in other domains of WT1. In the current proposal, Dr. Zhang will evaluate the functional consequences of these mutations and characterize the mechanisms associated with the growth/survival advantage and a higher propensity for chemotherapy resistance of WT1 mutations. She also aims to identify therapeutics with enhanced efficacy in the WT1 mutant setting. Using ex vivo inhibitor screening on primary leukemia patient samples, she has determined that inhibitors of BCL2 and RAF/ERK pathways demonstrated higher efficacy against WT1 mutant samples compared with controls. She will validate these findings using NRG mouse model. Finally, she will investigate the phenotypic, mechanistic, and therapeutics targeting WT1 combinatorial mutation. Dr. Zhang's long-term career goals include the establishment of an independent research lab focusing on systematic characterization of oncogenic mutations and chemotherapy resistance to better predict the clinical relevance of mutations and identify novel therapeutics to circumvent chemotherapy resistance. During the mentored phase, she will continue to receive excellent mentorship from Dr. Jeffrey Tyner, an expert on functional genomics and targeted therapy. She will receive co-mentorship from Dr. Ravi Majeti, an expert in leukemia stem cell biology, CRISPR editing, and high-fidelity xenotransplantation mouse models, which she will use in the current project. The proposed research will also be enhanced by guidance from Dr. Brian Druker, a pioneer in translational medicine and targeted therapies for cancer; and Dr. Shannon McWeeney who will provide guidance in bioinformatics analyses. Additionally, Dr. Tyner, Dr. Majeti, and the advisory team will assist her in navigating the transition to an independent faculty position.

项目总结/文摘