# Targeting protein acetylation as a therapeutic approach for MDS

> **NIH NIH R01** · BECKMAN RESEARCH INSTITUTE/CITY OF HOPE · 2020 · $432,500

## Abstract

Project Summary
Myelodysplastic syndromes (MDS) are hematopoietic disorders characterized by ineffective hematopoiesis,
peripheral cytopenias, and a propensity for progression to acute myeloid leukemia (AML). MDS remains
incurable by existing nontransplant therapy, which is the only option for MDS patients over 60 years old. An
increasing number of clonal-analysis studies provide direct evidence that, in MDS, cells of the entire bone
marrow are clonally derived from a single hematopoietic stem cell (HSC) or early myeloid progenitor. These
aberrant MDS hematopoietic stem and progenitor cells (HSPCs) reportedly resist therapy and expand causing
relapse. Thus, improved understanding of mechanisms regulating MDS HSPCs maintenance could foster
development of therapies targeting MDS HSPCs.
The DNA demethylation enzyme Tet methylcytosine dioxygenase 2 (TET2) reportedly protects normal HSCs
from transformation into disease-initiating clones in hematological malignancies. We recently found that protein
levels of SIRT1, a deacetylase that contributes to normal HSC maintenance under stress conditions,
significantly decreased in MDS CD34+ cells, a population highly enriched for MDS HSPCs. Using loss-of-
function and mutagenesis studies, we identified a novel mechanism that SIRT1-deficiency induces TET2
hyperacetylation, leading to TET2 dysfunction in MDS cells. We also found that SIRT1 activation blocked MDS
cell proliferation in a TET2-dependent manner. Importantly, our preliminary studies also show that TET2
acetylation levels increase in human MDS specimens expressing below normal SIRT1 protein levels.
Based on these findings, we hypothesize that, in the absence of TET2 mutations, SIRT1-deficiency induces
TET2 dysfunction due to unregulated hyperacetylation, enabling MDS HSPCs maintenance, and accordingly,
that SIRT1-induced TET2 deacetylation could ablate MDS HSPCs. To test our hypothesis, we will: 1)
determine the pathogenic roles of SIRT1 and TET2 in MDS maintenance using genetic mouse models; 2)
define upstream and downstream factors of the SIRT1/TET2 axis in MDS cells; and 3) determine whether
SIRT1 activation alone or in combination with a hypomethylating agent that is currently first-line treatment for
older, high risk MDS patients can ablate MDS HSPCs. We expect that our studies will uncover functional
interaction between SIRT1 and TET2 and reveal how both factors govern MDS HSPC growth and self-renewal.
These studies will close the knowledge gap relevant to how MDS-initiating clones acquire a growth advantage
during MDS development and may identify more effective therapeutic strategy for ablating MDS disease-
propagating cells by targeting SIRT1.

## Key facts

- **NIH application ID:** 9873989
- **Project number:** 5R01HL141336-03
- **Recipient organization:** BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
- **Principal Investigator:** LING LI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $432,500
- **Award type:** 5
- **Project period:** 2018-03-03 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9873989

## Citation

> US National Institutes of Health, RePORTER application 9873989, Targeting protein acetylation as a therapeutic approach for MDS (5R01HL141336-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9873989. Licensed CC0.

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