Targeting dysregulated transcriptome as therapy for post-myeloproliferative neoplasm (MPN) sAML
靶向转录组失调作为骨髓增殖后肿瘤 (MPN) sAML 的治疗方法
基本信息
- 批准号:10595080
- 负责人:
- 金额:$ 46.63万
- 依托单位:
- 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:2020-04-13 至 2025-03-31
- 项目状态:未结题
- 来源:
- 关键词:ATAC-seqAcetylationApoptoticAttenuatedBCL2 geneBCL2L1 geneBindingBinding SitesBromodomainBromodomains and extra-terminal domain inhibitorC-terminalCDK9 Protein KinaseCatalytic DomainCell Culture TechniquesCell LineCell SurvivalChIP-seqChromatinChromatin Remodeling FactorClinicalCyclin-Dependent Kinase InhibitorCyclin-Dependent KinasesDNA Polymerase IIDNA Sequence AlterationDNMT3aDependenceDisease ProgressionEZH2 geneElementsEnhancersEnzymesEpigenetic ProcessEvaluationExhibitsFamily memberGenesGenetic TranscriptionGrowthHematopoietic stem cellsHistonesIn VitroInduction of ApoptosisJAK1 geneJAK2 geneJanus kinaseLysineMCL1 geneMediatingMediatorMessenger RNAMutationMyelofibrosisMyeloproliferative diseaseNF-kappa BNeoplasm MetastasisOncogenesOutcomePIM1 genePatientsPhenotypePhosphorylationPositive Transcriptional Elongation Factor BPredispositionProductivityProtacProtein FamilyProteinsRELA geneRNARUNX1 geneReaderRefractoryRepressionResistanceSRSF2 geneSTAT3 geneSecondary acute myeloid leukemiaSerineSignal TransductionTP53 geneTechniquesTestingTherapeuticTimeTranscriptXenograft Modelantagonistc-myc Genescalreticulincell growthchemotherapycyclin T1epigenetic regulationepigenomegenomic profilesimprovedin vivoinhibitormimeticsnegative elongation factornovelpre-clinicalpreclinical efficacypromoterprotein expressionrecruitresistance mechanismstem cellstranscription factortranscriptometranscriptome sequencing
项目摘要
Myeloproliferative neoplasms with myelofibrosis (MPN-MF) exhibit constitutive activity of JAK-STAT signaling
due to mutations in JAK2, c-MPL or calreticulin genes. Additional mutations in chromatin/transcriptional
modifiers (epimutations) induce transformation to AML (sAML) in up to 20% of patients with MPN-MF. Lack of
significant activity of the JAK1 & 2 inhibitor (JAKi) ruxolitinib and of AML chemotherapy highlights the need to
develop and test novel agents and combinations that would improve clinical outcome in patients with post-
MPN sAML. Genetic alterations and dysregulated epigenome produce the dysregulated transcriptome
responsible for the transformed phenotype and therapy-refractoriness in post-MPN sAML blast progenitor
cells (BPCs). This dysregulated transcriptome is dependent on ‘chromatin-reader’ BET (bromodomain and
extra-terminal) proteins (BETPs), e.g., BRD4, and on its interactor pTEFb (positive transcription elongation
factor b), both recruited to super-enhancers and promoters of actively-transcribed oncogenes. Cyclin
dependent kinase 9 (CDK9), the catalytic subunit of pTEFb, phosphorylates RNA pol II (RNAP2), promoting
RNAP2-mediated mRNA transcript elongation of oncogenes essential for growth and survival of post-MPN
sAML BPCs. However, effects of BETP-CDK9 axis inhibition on active super-enhancers/enhancers and
promoters with resulting impact on the dysregulated transcriptome and survival have not been elucidated in
patient-derived (PD) sAML BPCs. Additionally, epigenetic mechanisms of resistance to CDK9 or BETP
inhibitor (CDK9i or BETi) treatment and their therapeutic abrogation in post-MPN sAML BPCs need
evaluation. Our preliminary studies demonstrate that CDK9i or BETP-antagonist (BETi and BETP-
PROTACs) treatment induces apoptosis of post-MPN sAML BPCs, which is associated with repression of
sAML-relevant oncogenes, e.g., c-MYC, STAT3/5, NFkB, Bcl-xL and MCL-1. We hypothesize that BETP-
antagonist and CDK9i-based combinations will repress the dysregulated transcriptome and oncogenes, and
with JAKi or BCL2/Bcl-xL inhibitor co-treatment, synergistically induce in vitro and in vivo lethality in PD, post-
MPN sAML BPCs. Specific aims of these studies are: Aim 1: To elucidate the effects of BETP-PROTAC
and CDK9i on active super-enhancers/enhancers (by ATAC-Seq and ChIP-Seq), mRNA transcriptome (by
RNA-Seq) and on protein expressions (by CyTOF), as well as determine their pre-clinical efficacy against
genetically-profiled, cultured cell lines and PD, post-MPN sAML BPCs. Aim 2: To determine lethal activity of
BETP-PROTAC and CDK9i-based combinations against JAKi-sensitive and JAKi-persister/resistant sAML
BPCs, utilizing in vitro cell cultures and in vivo xenograft models. Aim 3: To elucidate the dysregulated
epigenome and transcriptome as well as susceptibility to BETP-PROTAC-based combinations in BETi- or
CDK9i-persister/resistant post-MPN sAML BPCs.
骨髓增生性肿瘤伴骨髓纤维化(MPN-MF)表现出JAK-STAT信号的组成性活性
项目成果
期刊论文数量(0)
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会议论文数量(0)
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KAPIL BHALLA其他文献
KAPIL BHALLA的其他文献
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{{ truncateString('KAPIL BHALLA', 18)}}的其他基金
Novel combination therapy for AML expressing mutant RUNX1
表达突变体 RUNX1 的 AML 的新型联合疗法
- 批准号:
10698087 - 财政年份:2021
- 资助金额:
$ 46.63万 - 项目类别:
Novel combination therapy for AML expressing mutant RUNX1
表达突变体 RUNX1 的 AML 的新型联合疗法
- 批准号:
10276033 - 财政年份:2021
- 资助金额:
$ 46.63万 - 项目类别:
Novel combination therapy for AML expressing mutant RUNX1
表达突变体 RUNX1 的 AML 的新型联合疗法
- 批准号:
10473712 - 财政年份:2021
- 资助金额:
$ 46.63万 - 项目类别:
Biology and novel therapy of AML expressing somatic or germline mutant RUNX1
表达体细胞或种系突变体 RUNX1 的 AML 的生物学和新疗法
- 批准号:
10531564 - 财政年份:2020
- 资助金额:
$ 46.63万 - 项目类别:
Targeting dysregulated transcriptome as therapy for post-myeloproliferative neoplasm (MPN) sAML
靶向转录组失调作为骨髓增殖后肿瘤 (MPN) sAML 的治疗方法
- 批准号:
10364667 - 财政年份:2020
- 资助金额:
$ 46.63万 - 项目类别:
Biology and novel therapy of AML expressing somatic or germline mutant RUNX1
表达体细胞或种系突变体 RUNX1 的 AML 的生物学和新疗法
- 批准号:
10308449 - 财政年份:2020
- 资助金额:
$ 46.63万 - 项目类别:
BET protein antagonist-based targeted therapy of Mantle Cell Lymphoma
基于BET蛋白拮抗剂的套细胞淋巴瘤靶向治疗
- 批准号:
9888204 - 财政年份:2017
- 资助金额:
$ 46.63万 - 项目类别:
BET protein antagonist-based targeted therapy of Mantle Cell Lymphoma
基于BET蛋白拮抗剂的套细胞淋巴瘤靶向治疗
- 批准号:
10132260 - 财政年份:2017
- 资助金额:
$ 46.63万 - 项目类别:
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