# Targeting dysregulated transcriptome as therapy for post-myeloproliferative neoplasm (MPN) sAML

> **NIH NIH R01** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2020 · $475,860

## Abstract

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.

## Key facts

- **NIH application ID:** 9880963
- **Project number:** 1R01CA233457-01A1
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** KAPIL BHALLA
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $475,860
- **Award type:** 1
- **Project period:** 2020-04-13 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9880963

## Citation

> US National Institutes of Health, RePORTER application 9880963, Targeting dysregulated transcriptome as therapy for post-myeloproliferative neoplasm (MPN) sAML (1R01CA233457-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9880963. Licensed CC0.

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