# Cohesin Mutations in Acute Myelogenous Leukemia

> **NIH NIH R01** · VERSITI BLOOD HEALTH, INC. · 2021 · $376,691

## Abstract

Abstract: Acute Myelogenous Leukemia (AML) is a bone marrow-derived malignancy and remains a clinical
challenge, with long-term survival of approximately 50%. Improvements in AML therapy have predominantly
come through better supportive care and the improvements in allogeneic bone marrow transplantation, rather
than improved chemotherapy approaches. This plateauing in AML survival points to a need for better, targeted
therapies. Part of the difficulty with developing novel treatments to AML is that it is a heterogeneous disease,
with well over 250 different mutated genes, although any one patient has on average 13 somatic mutations.
Thus, developing a “unifying genetic signature” that drives AML remains elusive. To understand how mutations
found in AML contribute to leukemia development, we have chosen to focus on mutations in genes encoding
the cohesin complex. Cohesin mutations occur in approximately 10-20% of patients, but its role in
leukemogenesis is unknown. Our preliminary data demonstrate that cohesin loss causes increased self-
renewal in wild-type murine bone marrow, a hallmark of leukemia development. Interestingly, this increased
self-renewal is augmented in Npm1+/- after cohesin loss. While Npm1 mutations are the most common single
gene mutation in AML, Npm1-mutated mice rarely develop AML, implying additional mutations are required. In
both wild-type (WT) and Npm1-mutated bone marrow, cohesin loss causes epigenetic derepression of the self-
renewal associated transcription factor HoxA9. Given that the Polycomb Repressive Complex 2 (PRC2),
which mediates trimethylation of Histone 3 on Lysine 27 (H3K27me3), normally silences HoxA9 epigenetically
we hypothesize that cohesin haploinsufficiency promotes AML by derepressing PRC2 target genes.
The goal of this proposal is to use a combination of genome-wide approaches and genomic editing to
determine the mechanism by which cohesin mutations induce abnormal self-renewal and promote leukemia
development. In Aim 1 we will use chromatin immunoprecipitation coupled with next-generation sequencing
(ChIP-seq) to identify changes in PRC2 genomic localization after cohesin loss. In Aim 2, we will use circular
chromosomal conformational capture (4C) to identify which distal cis-regulatory elements (CREs) are normally
recruited to regulate HoxA9 expression, and the changes in distal CREs after cohesin loss. In Aim 3 we will
further characterize both in vitro and in vivo the effects of cohesin depletion on WT and Npm1cA/+ bone marrow.
Also in Aim 3, we will test the role of the histone methyltransferase Dot1l loss/inhibition in preventing HoxA9
expression and cohesin-depletion associated self-renewal. Collectively, the long-term goal of our studies is to
develop a novel mouse model of AML based upon loss of cohesin in Npm1cA AML, a combination of mutations
that represents a sizeable fraction of patients with AML. In addition, we will use this model to address
mechanistic question regarding how altered...

## Key facts

- **NIH application ID:** 10224847
- **Project number:** 5R01CA204231-05
- **Recipient organization:** VERSITI BLOOD HEALTH, INC.
- **Principal Investigator:** Sridhar Rao
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $376,691
- **Award type:** 5
- **Project period:** 2017-09-19 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10224847

## Citation

> US National Institutes of Health, RePORTER application 10224847, Cohesin Mutations in Acute Myelogenous Leukemia (5R01CA204231-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10224847. Licensed CC0.

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