权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

CUX1 pioneer factor activity is required to prevent myeloid leukemogenesis

CUX1先锋因子活性是预防髓系白血病发生所必需的

基本信息

批准号：
10292902
负责人：
Jeffrey Lee Kurkewich
金额：
$ 3.6万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-01 至 2021-12-05
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10292902
关键词：
AKT Signaling Pathway AML/MDS Acute Myelocytic Leukemia Advisory Committees Affect Allogeneic Bone Marrow Transplantation Bioinformatics Biological Assay Biometry Bone Marrow Diseases Bone Marrow Neoplasms CD34 gene CRISPR/Cas technology Cell Differentiation process Cellular biology Chicago Chromatin Chromosome 7 Chromosome Arm Chromosome Deletion Chromosome abnormality Chromosomes Clinical Complex Coupled Cytogenetics DNA-Binding Proteins Data Development Disease Distal Dysmyelopoietic Syndromes Dysplasia Enhancers Environment Equilibrium Erythroid Erythropoiesis Etiology Euchromatin Gene Expression Gene Expression Regulation Genes Genetic Genetic Screening Genomic approach Genomics Goals Group Meetings Health Care Costs Hematologic Neoplasms Hematopoiesis Hematopoietic Hematopoietic stem cells Human Human Cell Line Individual International K-562 Knowledge Life Maintenance Malignant Neoplasms Mentors Modeling Molecular Molecular Target Monosomy 7 Mus Mutate Mutation Myelogenous Myeloproliferative disease Neoplasms Normocytic Anemia Nucleosomes Outcome PI3K/AKT Pathway interactions Patient Care Patients Phenotype Prognosis Public Health Quality of life Recurrence Reporting Research Research Proposals Resistance Resources Risk Role SWI/SNF Family Complex Science Scientist Signal Pathway Supervision Techniques Testing Training Transcription Coactivator Transcriptional Regulation Treatment Protocols Tumor Suppressor Genes United States Universities base cancer genomics care outcomes career career development chromatin remodeling chromosome 7 loss chromosome 7q loss conventional therapy cytopenia disorder risk effective therapy erythroid differentiation experience experimental study functional genomics genetic signature genome editing genome-wide hematopoietic differentiation high risk improved innovation knock-down leukemic transformation leukemogenesis loss of function mutation myeloid leukemia cell novel novel therapeutic intervention prevent recruit standard of care stem cell fate stem cell function stem cell proliferation symposium transcription factor transcriptome sequencing transplantation therapy

项目摘要

PROJECT SUMMARY/ABSTRACT Myeloid malignancies comprise a heterogenous group of life-threatening clonal bone marrow neoplasms that affect over 150,000 people in the United States alone. Current treatment options for acute myeloid leukemia and myelodysplastic syndrome are limited, and have only modest benefits for high-risk patients. Deletion of part or all of chromosome 7 [-7/del(7q)] is a common cytogenetic change associated with adverse-risk prognosis and resistance to conventional therapies. The underlying genetic mechanism(s) in [-7/del(7q)] that leads to high- risk myeloid disease has remained a critical but unsolved question in the field. However, our lab has identified a tumor suppressor gene, CUX1, encoded on 7q that is recurrently mutated in myeloid disorders. CUX1 loss-of-function mutations are associated with a poor clinical prognosis independent of chromosome 7 cytogenetic abnormalities. Despite these findings, the endogenous role of CUX1 during hematopoiesis, and the mechanism by which it suppresses leukemia transformation, remain unclear, presenting a major barrier to understanding how CUX1 haploinsufficiency leads to high-risk disorders. My preliminary data suggest that CUX1 is required in human hematopoietic stem and progenitor cells (HSPCs) to suppress proliferation and promote erythroid development. Furthermore, my data indicate that CUX1 cooperates with the SWI/SNF nucleosome remodeling complex in HSPCs to regulate chromosome accessibility and promote erythroid gene expression. This proposal will utilize innovative functional genomic approaches, coupled with developmental assays with primary human HSPCs, to define the molecular and cellular mechanisms by which CUX1 regulates HSPC biology and differentiation. Fulfilling this gap in knowledge will be critical to aiding the development of new therapeutic strategies for high-risk myeloid malignancies. This proposal will also provide me with the expertise necessary to achieve my long-term goal of becoming an independent scientist in the field of cancer genomics. To oversee my project and career development, I have enlisted a team of highly qualified mentors with a breadth of experience in myeloid neoplasia, hematopoiesis, genomics, bioinformatics, and biostatistics. Together we have developed a robust training plan that incorporates individual and group meetings, didactic coursework, institutional resources and seminars, and attendance at international conferences to prepare me for a career in academic science.

项目总结/文摘