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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：
KAPIL BHALLA
金额：
$ 46.63万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
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：
https://reporter.nih.gov/project-details/10595080
关键词：
ATAC-seq Acetylation Apoptotic Attenuated BCL2 gene BCL2L1 gene Binding Binding Sites Bromodomain Bromodomains and extra-terminal domain inhibitor C-terminal CDK9 Protein Kinase Catalytic Domain Cell Culture Techniques Cell Line Cell Survival ChIP-seq Chromatin Chromatin Remodeling Factor Clinical Cyclin-Dependent Kinase Inhibitor Cyclin-Dependent Kinases DNA Polymerase II DNA Sequence Alteration DNMT3a Dependence Disease Progression EZH2 gene Elements Enhancers Enzymes Epigenetic Process Evaluation Exhibits Family member Genes Genetic Transcription Growth Hematopoietic stem cells Histones In Vitro Induction of Apoptosis JAK1 gene JAK2 gene Janus kinase Lysine MCL1 gene Mediating Mediator Messenger RNA Mutation Myelofibrosis Myeloproliferative disease NF-kappa B Neoplasm Metastasis Oncogenes Outcome PIM1 gene Patients Phenotype Phosphorylation Positive Transcriptional Elongation Factor B Predisposition Productivity Protac Protein Family Proteins RELA gene RNA RUNX1 gene Reader Refractory Repression Resistance SRSF2 gene STAT3 gene Secondary acute myeloid leukemia Serine Signal Transduction TP53 gene Techniques Testing Therapeutic Time Transcript Xenograft Model antagonist c-myc Genes calreticulin cell growth chemotherapy cyclin T1 epigenetic regulation epigenome genomic profiles improved in vivo inhibitor mimetics negative elongation factor novel pre-clinical preclinical efficacy promoter protein expression recruit resistance mechanism stem cells transcription factor transcriptome transcriptome 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