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

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)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

KAPIL BHALLA其他文献

KAPIL BHALLA的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ 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:
Novel Targeted Therapy for AML
AML 的新型靶向治疗
  • 批准号:
    9247879
  • 财政年份:
    2015
  • 资助金额:
    $ 46.63万
  • 项目类别:
Novel Targeted Therapy for AML
AML 的新型靶向治疗
  • 批准号:
    8655146
  • 财政年份:
    2013
  • 资助金额:
    $ 46.63万
  • 项目类别:

相似海外基金

Investigating the functions of histone acetylation in genome organization and leukemogenesis
研究组蛋白乙酰化在基因组组织和白血病发生中的功能
  • 批准号:
    EP/Y000331/1
  • 财政年份:
    2023
  • 资助金额:
    $ 46.63万
  • 项目类别:
    Research Grant
Gene Modulation of Acetylation Modifiers to Reveal Regulatory Links to Human Cardiac Electromechanics
乙酰化修饰剂的基因调节揭示与人类心脏机电的调节联系
  • 批准号:
    10677295
  • 财政年份:
    2023
  • 资助金额:
    $ 46.63万
  • 项目类别:
Novel roles of PDK2 in heart failure: Regulation of mitochondrial nuclear crosstalk via metabolic regulation and histone acetylation
PDK2 在心力衰竭中的新作用:通过代谢调节和组蛋白乙酰化调节线粒体核串扰
  • 批准号:
    10635599
  • 财政年份:
    2023
  • 资助金额:
    $ 46.63万
  • 项目类别:
Regulation of hepatic lysine N-acetylation by cysteine proximity due to alcohol toxicity
酒精毒性导致的半胱氨酸接近对肝脏赖氨酸 N-乙酰化的调节
  • 批准号:
    10752320
  • 财政年份:
    2023
  • 资助金额:
    $ 46.63万
  • 项目类别:
Histone Acetylation Regulates Microglial Innate Immune Memory
组蛋白乙酰化调节小胶质细胞先天免疫记忆
  • 批准号:
    478927
  • 财政年份:
    2023
  • 资助金额:
    $ 46.63万
  • 项目类别:
    Operating Grants
Dysregulation of Histone Acetylation in Parkinson's Disease
帕金森病中组蛋白乙酰化的失调
  • 批准号:
    10855703
  • 财政年份:
    2023
  • 资助金额:
    $ 46.63万
  • 项目类别:
Obesity-related hypertension: the contribution of PPAR gamma acetylation and asprosin
肥胖相关高血压:PPAR γ 乙酰化和白脂素的贡献
  • 批准号:
    10654210
  • 财政年份:
    2023
  • 资助金额:
    $ 46.63万
  • 项目类别:
The role N-terminal acetylation in dilated cardiomyopathy and associated arrhythmia
N-末端乙酰化在扩张型心肌病和相关心律失常中的作用
  • 批准号:
    10733915
  • 财政年份:
    2023
  • 资助金额:
    $ 46.63万
  • 项目类别:
In vivo tracing of hepatic ethanol metabolism to histone acetylation: role of ACSS2 in alcohol-induced liver injury
肝脏乙醇代谢与组蛋白乙酰化的体内追踪:ACSS2 在酒精性肝损伤中的作用
  • 批准号:
    10667952
  • 财政年份:
    2023
  • 资助金额:
    $ 46.63万
  • 项目类别:
The function of TWIST1 acetylation in cell fate and tissue development
TWIST1 乙酰化在细胞命运和组织发育中的作用
  • 批准号:
    10726986
  • 财政年份:
    2023
  • 资助金额:
    $ 46.63万
  • 项目类别:
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了