# The cohesin complex as a tumor suppressor in myeloid leukemia

> **NIH NIH R01** · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · 2021 · $488,648

## Abstract

ABSTRACT
Acute myeloid leukemia (AML) is the most common adult leukemia characterized by excessive proliferation of
abnormal myeloid progenitors. AML continues to have a dismal survival rate amongst all subtypes of leukemia
(<50% five-year overall survival rate), which can largely be attributed to limited advances in treatment
regimens that, for the last decades, have relied on the use of two non-targeted cytotoxic drugs: cytarabine and
anthracycline. Large-scale sequencing efforts have shed new light on genetic and epigenetic determinants of
AML. Interestingly, these studies identified a frequent co-occurrence of somatic mutation between genes
encoding cohesin complex subunits (such as STAG2, SMC1A, RAD21 and SMC3) and well-characterized
AML oncogenic triggers, such as FLT3-ITD, TET2, and NPM1. Recent work has demonstrated an important
role for the cohesin complex in normal stem/progenitor self-renewal and differentiation, gene regulation, and
suppression of myeloproliferative neoplasms and AML, despite the precise mechanisms underlying these
functions remaining poorly understood. It is believed that cohesin may suppress tumor formation by regulating
chromatin looping at loci critical for self-renewal and myeloid progenitor differentiation. Utilizing established
models of murine and human AML, this application focuses on the molecular mechanisms of cohesin-
dependent myeloid tumor-suppression, with an emphasis on understanding novel treatment approaches that
can exploit these functions. Using established protocols for identifying genome-wide changes in chromatin
topology and gene expression, we propose to undertake an extensive characterization of cohesin-regulated
chromatin changes driving AML. Furthermore, recent studies have identified inhibition of HDAC8 and poly-ADP
ribose polymerase (PARP) as an attractive targeted treatment approach for cohesin-mutated AML patients.
Here we investigate the application of targeted agents in cohesin-deficient AML whilst extensively mapping the
mechanisms-of-action underlying these specific treatments. Ultimately, this project aims to generate novel, pre-
clinical disease models of cohesin-mutated AML with strong mechanistic insights into the tumor-suppressive
function of this complex.

## Key facts

- **NIH application ID:** 10169373
- **Project number:** 5R01CA216421-05
- **Recipient organization:** NEW YORK UNIVERSITY SCHOOL OF MEDICINE
- **Principal Investigator:** Iannis Aifantis
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $488,648
- **Award type:** 5
- **Project period:** 2017-06-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10169373

## Citation

> US National Institutes of Health, RePORTER application 10169373, The cohesin complex as a tumor suppressor in myeloid leukemia (5R01CA216421-05). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10169373. Licensed CC0.

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