Cohesin Mutations in Core-Binding Factor Acute Myeloid Leukemia
核心结合因子急性髓系白血病的粘连蛋白突变
基本信息
- 批准号:10430046
- 负责人:
- 金额:$ 5.18万
- 依托单位:
- 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:2019-07-01 至 2023-06-30
- 项目状态:已结题
- 来源:
- 关键词:AML1-ETO fusion proteinATAC-seqAcute Myelocytic LeukemiaAdult Acute Myeloblastic LeukemiaAllelesAnimal ModelApoptosisAutomobile DrivingBasic ScienceBindingBone Marrow CellsBone Marrow TransplantationBone marrow failureCBFB geneCBFbeta-MYH11 fusion proteinCSPG6 geneCell NucleusCellsChIP-seqChildhoodChimeric ProteinsChromatinChromosomal RearrangementChromosome 16Chromosome abnormalityChromosomesClinicalComplexCore-Binding FactorDNADNA BindingDataDependenceDevelopmentDiseaseEngineeringEquipmentExhibitsFusion Oncogene ProteinsFutureGene ExpressionGene set enrichment analysisGeneticGenetic TranscriptionGenomicsGoalsHematopoiesisIn VitroKnowledgeLeadLearningMalignant NeoplasmsMentorsMolecularMusMutationMyelogenousOncogenesOncogenicOutcomePathway interactionsPatientsPhenotypePhysiciansPlayPrognosisRUNX1 geneRegulationRelapseResearchResourcesRoleScientistSigns and SymptomsTestingToxic effectTrainingTransplantationUp-RegulationXCL1 genebasecellular transductionchemotherapyclinical prognosticcohesindesignexperimental studygenetic makeupgenetic signaturein vivoindividual patientleukemialeukemic transformationleukemogenesismemberpressureprognosticself-renewalt(821)(q22q22)targeted treatmenttherapeutic targettranscriptometranscriptome sequencingtreatment strategyvirtual
项目摘要
Abstract
Core-binding factor leukemia represents a subtype of AML and encompasses 30% of pediatric and 15% of adult
AMLs. The core-binding factor complex is essential in the regulation of normal hematopoiesis and is composed
of AML1 (also known as RUNX1) and CBFB. Chromosomal alterations involving the core-binding factor
complex are well-known “drivers” of leukemia development and have similar clinical and prognostic
implications. A t(8;21) leads to the fusion oncoprotein AML1-ETO and an inv(16) leads to CBFB-MYH11.
Surprisingly, these mutations alone do not induce AML in animal models, suggesting additional “hits” are
required. Mutations in one of four members of the cohesin complex (SMC1a, SMC3, RAD21, STAG1) are
commonly found in patients with AML and frequently (18-20%) co-occur with AML1-ETO, but never with
CBFB-MYH11. This suggests a selective pressure for the presence or absence of cohesin mutations depending
upon the driver oncogene. By learning more about the genetic makeup of these leukemias and how additional
mutations promote leukemogenesis, we can develop targeted therapies which will reduce both toxicity and the
relapse rate compared to existing treatments. We hypothesize that cohesin mutations synergize with
AML1-ETO during leukemic transformation, whereas cohesin mutations and CBFB-MYH11
form a synthetic lethal interaction. In Aim 1, in vivo transplant studies will be performed with AML1-
ETO;SMC3+/+ compared to AML1-ETO;SMC3+/- while CBFB-MYH11;SMC3+/+ and CBFB-MYH11; SMC3+/- will
be studied in vitro. In Aim 2, molecular studies will be performed to delve into the mechanisms driving
leukemia. ChIP-sequencing will be performed to identify changes in AML1-ETO genomic occupancy upon
introduction of cohesin haploinsufficiency. ATAC-seq and RNA-seq will be performed to identify changes in
chromatin accessibility and transcriptome of CBFB-MYH11 due to cohesin haploinsufficiency. Our preliminary
studies indicate that the loss of cohesin augments in vitro self-renewal of AML1-ETO transduced cells.
Preliminary ATAC-sequencing demonstrates that several motifs implicated in myeloid development (RUNX1,
GATA2, ERG, PU.1) are enriched in the AML1-ETO;SMC3+/- background. Further, RNA sequencing reveals
upregulation of the MYC, Rb, and E2F oncogenic gene signatures in AML1-ETO;SMC3+/- compared to SMC3+/+.
Training potential abounds for a future physician scientist within this proposal as it involves using clinical
observations to generate a hypothesis, design a research plan and develop clinical correlations based upon the
results of basic science research. Mentoring support will be easily accessible throughout this training, as will be
all necessary equipment and resources needed to complete this project.
摘要
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
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Katelyn E Heimbruch其他文献
Defining the Impacts of Iron Overload in Children Receiving Hematopoietic Stem Cell Transplantation for Non-Malignant Hematologic Disorders: A Multicenter Analysis
- DOI:
10.1182/blood-2024-204339 - 发表时间:
2024-11-05 - 期刊:
- 影响因子:
- 作者:
Nora M. Gibson;Sandra Amaral;Jesse Y Hsu;Nhat Nguyen;Meghan Haney;Katelyn E Heimbruch;Anthony Sabulski;Kimberly Ann Davidow;Katherine Lind;Samantha Scanlon;Heather Alva;L. Charles Bailey;Timothy S. Olson;Janet L. Kwiatkowski - 通讯作者:
Janet L. Kwiatkowski
Cohesin Haploinsufficiency Drives Leukemic Initiation through Fli1 Upregulation in Inv(16) AML
- DOI:
10.1182/blood-2024-200326 - 发表时间:
2024-11-05 - 期刊:
- 影响因子:
- 作者:
Alison E Meyer;Katelyn E Heimbruch;Kirthi Pulakanti;Cary Stelloh;Josiah Murray;John A Pulikkan;Sridhar Rao - 通讯作者:
Sridhar Rao
Katelyn E Heimbruch的其他文献
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{{ truncateString('Katelyn E Heimbruch', 18)}}的其他基金
Cohesin Mutations in Core-Binding Factor Acute Myeloid Leukemia
核心结合因子急性髓系白血病的粘连蛋白突变
- 批准号:
10166800 - 财政年份:2019
- 资助金额:
$ 5.18万 - 项目类别:
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