# Biology and novel therapy of AML expressing somatic or germline mutant RUNX1

> **NIH NIH R01** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2021 · $496,911

## Abstract

Project Summary:
RUNX1 is the DNA-binding subunit of the core binding factor (CBF) complex and a master-regulator
transcription factor, which is involved in normal and malignant hematopoiesis. Somatic, heterozygous RUNX1
mutations commonly occur in Myelodysplastic Syndrome (MDS) (10%), as well as in secondary (s) or de novo
AML (~10%). Germline mutations in RUNX1 cause the highly penetrant (~40%) autosomal dominant, Familial
Platelet Disorder (FPD), which can evolve into myeloid malignancy (FPD-MM). Majority of mutant (mt) RUNX1
behave mostly as loss of function mutations, conferring relative therapy-resistance and poorer survival in
patients with AML. Consequently, there is a strong unmet need to develop novel therapies for AML expressing
somatic or germline mtRUNX1. Our preliminary studies have demonstrated for the first time that shRNA-
mediated knockdown of RUNX1 (mutant and wild-type) or disruption of its binding to CBFβ induces greater
lethality in AML progenitor cells (HPCs) expressing mtRUNX1 compared to wild-type (wt) RUNX1. We also
found that the +24kb enhancer (eR1) within the intragenic super-enhancer (SE) of RUNX1 regulates its
transcription in AML cells. The chromatin reader BET (Bromodomain Extra-terminal) protein (BETP) BRD4
promotes transcription of RUNX1 and its targets. BRD4 degradation or eviction from chromatin, or gene-editing
of the +24kb RUNX1 eR1, induces lethality in AML cells. By determining and utilizing the mRNA signature from
RUNX1-depleted (by shRNA) AML cells, we queried, through LINCS1000-CMap (Connectivity Mapping)
analysis, for expression mimickers (EMs). We identified novel EMs that repress RUNX1 and its targets and
induce significantly more apoptosis of AML cells expressing mtRUNX1 versus wtRUNX1. Therefore, the
hypothesis motivating our studies is that knocking down of levels of RUNX1 and its targets will induce lethality
not only in AML blasts expressing somatic mtRUNX1 but also in FPD/MM HPCs expressing germline
mtRUNX1. The specific aims of studies proposed are: AIM 1: To determine impact on active enhancers,
transcriptome and pre-clinical in vitro and in vivo efficacy of BETP antagonist along with its co-repression of
RUNX1, BCL2 and CDK6, alone or in combination with BCL2 or CDK6 inhibitor, in AML blasts and patient-
derived xenograft (PDX) models expressing somatic mutant RUNX1. Additionally, we will evaluate pre-clinical
efficacy of co-targeting CRISPR-Cas9 screen-discovered top ‘druggable’ dependencies along with BETP
antagonist against AML blasts expressing somatic mtRUNX1. AIM 2: To elucidate pre-clinical in vitro and in
vivo efficacy of the EMs homoharringtonine (omacetaxine) or fedratinib alone and in combination with BETP
antagonists against patient-derived AML blasts and PDX models expressing somatic mtRUNX1. AIM 3: To
determine pre-clinical in vitro and in vivo efficacy of selected EMs that repress RUNX1 and its targets against
patient-derived HPCs from FPD-MM expressing germline mtRUNX1 and ot...

## Key facts

- **NIH application ID:** 10098865
- **Project number:** 1R01CA255721-01
- **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:** 2021
- **Award amount:** $496,911
- **Award type:** 1
- **Project period:** 2020-12-01 → 2025-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10098865

## Citation

> US National Institutes of Health, RePORTER application 10098865, Biology and novel therapy of AML expressing somatic or germline mutant RUNX1 (1R01CA255721-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10098865. Licensed CC0.

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