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

In Vivo Functional Analysis of Chromosome 7q22 Deletions in Myeloid Malignancies

骨髓恶性肿瘤中染色体 7q22 缺失的体内功能分析

基本信息

批准号：
9924474
负责人：
KEVIN M. SHANNON
金额：
$ 33.87万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-05-22 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9924474
关键词：
1 year old Abnormal Cell Acute Myelocytic Leukemia Address Adolescent Adult Aftercare Alkylating Agents Blood CHEK2 gene CRISPR/Cas technology Cancer Survivor Cells Child Childhood Chromosome 7 Chromosome Arm Chromosome Band Chromosome Deletion Chromosome abnormality Chromosomes Complex Cytogenetic Analysis Cytogenetics DNA DNA Damage DNA sequencing Data Defect Development Drug resistance Dysmyelopoietic Syndromes Engineering Ethylnitrosourea Exhibits Exposure to Fluorescent in Situ Hybridization Genes Genetic Genetic Transcription Genetically Engineered Mouse Genomic DNA Germ Lines Growth Hematologic Neoplasms Hematological Disease Hematopoiesis Hematopoietic Hematopoietic stem cells Human Impairment Inherited Lymphoid Malignant - descriptor Malignant Childhood Neoplasm Malignant Neoplasms Modeling Modernization Molecular Monosomy 7 Mouse Strains Mus Mutagens Mutation Myelogenous Myeloproliferative disease Output Pathogenesis Patients Phenotype Population Populations at Risk Predisposition Radiation therapy Reagent Recurrence Refractory Resources Second Primary Cancers Solid Specimen System Testing Therapeutic Treatment Protocols Tumor Suppressor Genes Work aged cancer genome cell behavior chromosome 7 loss chromosome 7q loss clinical risk cohort genetic analysis genome-wide genome-wide analysis high risk in vivo leukemia leukemic transformation leukemogenesis mouse development mutant novel novel therapeutic intervention reconstitution response self-renewal transcriptome young adult

项目摘要

ABSTRACT Recurring losses of large chromosomal regions are a hallmark of pediatric and adult cancer genomes that pose exceptional challenges for uncovering how these deletions contribute to malignant growth. Monosomy 7 (-7) and del(7q) (-7/del(7q)) are recurring cytogenetic abnormalities in de novo myeloid malignancies that are strongly associated with cases of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) arising in children and in adolescent/young adult (AYA) patients with inherited cancer predispositions and in those who develop myeloid malignancies after treatment for a primary cancer. Therapy-induced MDS and AML (t-MDS and t-AML) are particularly relevant to the pediatric and AYA population due to modern intensive treatment protocols for many solid cancers, which are frequently curative. As a result, there is a large and growing population of “at risk” pediatric and AYA cancer survivors. Unfortunately, t-MDS/t-AML and other myeloid malignancies with chromosome 7 deletions are highly refractory to current therapies. Extensive cytogenetic and genome wide analysis studies implicate deletions of chromosome band 7q22 in leukemogenesis; however, sequencing studies and transcriptome analysis did not reveal frequent homozygous inactivation of any candidate 7q tumor suppressor gene in myeloid malignancies. These data implicate haploinsufficiency for one or more 7q genes in leukemogenesis, which pose formidable challenges for elucidating the underlying molecular mechanisms. To address this fundamental problem, we deployed chromosome engineering to create 5A3+/del and 5G2+/del mice, which respectively harbor deletions in mouse chromosome bands 5A3 and 5G2. These deletions span ~4 MB of genomic DNA that is syntenic to the most common 7q22 deletions identified in human patients. 5A3+/del hematopoietic stem and progenitor cells (HSPC) exhibit “preleukemic” abnormalities, but these mice do not spontaneously develop MDS or AML. Preliminary studies of 5G2+/del mice also revealed HSPC abnormalities and exposing this strain to N-ethyl-N-nitrosourea (ENU) accelerated the development of hematologic cancer. We will utilize these novel models of 7q22 deletions to pursue the following specific aims: (1) to functionally interrogate hematopoiesis in 5G2+/del and 5A3+/del/5G2+/del mice and to observe cohorts of mice for the development of myeloid malignancies; (2) to investigate the effects of DNA damaging agents on 5A3+/del/5G2+/del HSPC; and, (3) to model the complex genetics of myeloid malignancies with -7/del(7q) by introducing cooperating mutations into 5A3+/del/5G2+/del HSPC and assessing the phenotypic and functional consequences in vivo. Genetically engineered mice that accurately model recurrent chromosome band 7q22 deletions found in human myeloid malignancies are a versatile system for performing functional studies and testing new therapeutic strategies.

摘要