# Investigating novel synthetic lethal epigenetic interactions in Acute Myeloid Leukemia

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2022 · $377,046

## Abstract

Project Summary/Abstract
Acute myeloid leukemia (AML) is a hematopoietic malignancy characterized by aberrant self-renewal and
blocked differentiation of myeloid progenitor cells. Many of the oncogenic drivers of AML converge in
dysregulation of epigenetic and transcriptional regulation pathways, generating de novo dependencies on
these regulators. A handful of epigenetic dependencies have been identified in AML, however, single-agent
inhibitors against epigenetic regulators have shown limited therapeutic efficacy in patients with AML. To
improve our limited understanding of epigenetic-related synergistic genetic interactions in AML, we developed
a highly efficient CRISPR-Cas12a-based method enabling us to perform double deletion genetic screening.
Our preliminary studies identified and validated two pairs of novel interacting synthetic sick combinations of
epigenetic regulators in AML: bromodomain containing protein 9 (BRD9) and Jumonji domain-containing
protein 6 (JMJD6) as well as the lysine acetyltransferase 6 (KAT6) and JMJD6. JMJD6 is a bi-functional
arginine demethylase and lysyl-hydroxylase regulating transcription enhancer activation and was identified in
both synergistic pairs of epigenetic factor deletions. BRD9 is a component of chromatin remodeling SWI/SNF
complex and was previously identified as an AML specific dependency. KAT6A is a histone acetyltransferase
and transcriptional co-activator. We hypothesize that BRD9/JMJD6 and KAT6A/JMJD6 interact synergistically
at the level of transcription and chromatin. The presence of JMJD6 in both interactions suggests that JMJD6-
deficiency sets up a unique transcription and chromatin state that sensitizes AML cells to distinct epigenetic
stresses. In Aim 1, we will investigate the synthetic sick interactions of BRD9/JMJD6 and KAT6A/JMJD6 in
vitro and in vivo and in Aim 2, we will dissect the AML-specific synthetic sick interactions of BRD9/JMJD6 and
KAT6A/JMJD6 at the molecular level. Our proposed studies will offer basic mechanistic insight into how these
novel AML synthetic sick epigenetic interactions sustain AML pathogenesis. Successful completion of the
proposed studies holds significant promise towards developing innovative epigenetic pathway-directed
therapies and revealing fundamental biological insights into the pathogenesis of AML.
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## Key facts

- **NIH application ID:** 10364944
- **Project number:** 1R01CA258904-01A1
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** JUNWEI SHI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $377,046
- **Award type:** 1
- **Project period:** 2021-12-13 → 2026-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10364944

## Citation

> US National Institutes of Health, RePORTER application 10364944, Investigating novel synthetic lethal epigenetic interactions in Acute Myeloid Leukemia (1R01CA258904-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10364944. Licensed CC0.

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