# Novel combination therapy for AML expressing mutant RUNX1

> **NIH NIH R01** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2021 · $534,187

## Abstract

With current treatment regimens, long-term remission rates for adult patients with high risk
Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML) are 15-25%. RUNX1 is the DNA-
binding subunit of the core-binding factor (CBF) complex and a master-regulator transcription factor
involved in hematopoiesis. Majority of mutant (mt) RUNX1 are missense, large deletions or truncation-
mutations, behaving mostly as loss of function (LOF) mutations. Presence of mtRUNX1 confers relative
therapy-resistance and poorer survival in patients with MDS/AML. The germline mutations and deletions
in RUNX1 cause the highly penetrant (~40%) Familial Platelet Disorder with a propensity to evolve into
MDS or AML. Lack of specific targeted therapy, coupled with resistance to standard therapy may account
for poorer prognosis and outcome in MDS/AML expressing somatic or germline mtRUNX1. Therefore,
there is an unmet need to develop novel targeted therapies for MDS/AML expressing mtRUNX1. Our
preliminary studies demonstrate that knockdown of RUNX1 induces significantly more in vitro lethality in
AML blasts expressing mtRUNX1 versus wild type (wt) RUNX1. Utilizing RNA-Seq signature of RUNX1
knockdown and querying the LINCS1000-CMap (Connectivity-Mapping) datasets, we identified
homoharringtonine (HHT) among the top expression mimickers (EMs). Consistent with observations that
presence of mtRUNX1 impairs ribosomal biogenesis (RiBi), treatment with HHT or its semisynthetic
analog omacetaxine mepesuccinate (OM), which inhibit protein translation, preferentially exerted more
lethality in vitro and efficacy in vivo in models of AML expressing mtRUNX1. This was associated with
repression of RUNX1 and its targets, as well as attenuation of short-lived proteins including c-Myc and
MCL-1. Notably, co-treatment with OM and venetoclax (Ven) induced synergistic lethality and superior in
vivo efficacy in xenograft models of AML expressing mtRUNX1. Therefore, our Overarching hypothesis
motivating studies proposed is that targeted combination of OM and Ven will yield high remission rates
and improved survival, correlating with specific genetic and gene-expression signatures in patients with
high-risk MDS/AML expressing mtRUNX1. Specific aims of studies proposed are: AIM 1: To conduct a
Phase Ib/II clinical trial of co-treatment with OM and Ven in patients with high risk MDS or AML expressing
mtRUNX1. AIM 2: To determine correlates of efficacy/resistance to co-treatment with OM and Ven,
including genetic-lesions architecture (via NextGen and scDNA sequencing), epigenetic and gene-
expression signature (via RNA-Seq, RPPA and CyTOF analyses) and impaired RiBi features in MDS/AML
cells of patients enrolled on the Phase Ib/II trial. AIM 3: To determine pre-clinical efficacy of additional
OM-based combinations with BET or CDK9 inhibitor, as well as with novel targeted agents directed
against druggable hits nominated through an in vitro protein domain-specific CRISPR-gRNA screen.

## Key facts

- **NIH application ID:** 10276033
- **Project number:** 1R01CA262636-01
- **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:** $534,187
- **Award type:** 1
- **Project period:** 2021-09-01 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10276033

## Citation

> US National Institutes of Health, RePORTER application 10276033, Novel combination therapy for AML expressing mutant RUNX1 (1R01CA262636-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10276033. Licensed CC0.

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