# Role of epigenetic alterations in the bone marrow niche to aging-related hematopoietic clonality leading to IDH mutant MDS and AML

> **NIH NIH R56** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2021 · $332,100

## Abstract

Project Summary/Abstract
Isocitrate dehydrogenase 1 and 2 (IDH1/2) alterations are gain-of-function mutations that drive the synthesis of
the oncometabolite 2-hydroxyglutarate (2HG) which induces chromatin abnormalities, including globally altered
histone and DNA methylation profiles in MDS (and AML) cells. However, IDH1 and IDH2 mutations are not by
themselves sufficient to cause MDS. In addition, IDH1 and IDH2 mutations are detected in expanded clones in
aging healthy humans, a phenomenon termed “clonal hematopoiesis” that confers increased risk for MDS and
AML development. These observations suggest a) that IDH1/2 mutations require additional cooperative signals
to become fully transforming; and b) that such signals may accumulate with aging and potentiate the
transformation to MDS (or AML). We and others have demonstrated that the bone marrow stroma is a critical
regulator of the development of hematological myeloid malignancies, actively promoting their development or
progression. In investigating this possibility in IDH1/2-mutant MDS/AML, we found that 2HG is elevated in the
bone marrow plasma of MDS patients carrying IDH mutations as compared to MDS patients without such
mutations. Methylome analysis of bone marrow stromal cells from a cohort of 4 MDS/AML patients with and 4
without IDH mutations showed differential hypermethylation in the stroma of IDH1 and IDH2-mutant patients as
compared to IDH1 and IDH2 wild type patients. Integrative analysis of these results with RNAseq data from the
same subjects and preliminary in vivo analysis suggests stromal cell candidate genes that may affect IDH1/2-
related transformations. We hypothesize that IDH1 and IDH2 mutations in hematopoietic cells cooperate
with signals from the bone marrow niche that transform IDH-harboring HSCs to dysplastic cells and
promote MDS development. Such malignant signals from the marrow stroma may contribute to the clonal
hematopoiesis with aging and the transformation of pre-existing mutant IDH1/2 clones to dysplastic ones. We
will examine whether epigenetically modified stroma interacts with IDH1/2 mutant HSCs to promote their
leukemic potential in MDS/AML; and correlate with response to treatment; determine whether epigenetic
modifications in the aging bone marrow stroma support transformation of IDH1/2 mutated hematopoietic cells
to MDS/AML-initiating events; and, expand the methylome analysis of the stroma to allow for integrative
analyses with expression and promoter binding profiling that may uncover new stromal components of IDH1/2
transformation. These studies may identify stroma-derived signals that may be targeted therapeutically in
combination with current IDH1/2 inhibitors to improve treatment of IDH1/2 mutant MDS patients or, in the
future, to prevent MDS development.

## Key facts

- **NIH application ID:** 10490483
- **Project number:** 1R56AG070121-01A1
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** STAVROULA KOUSTENI
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $332,100
- **Award type:** 1
- **Project period:** 2021-09-30 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10490483

## Citation

> US National Institutes of Health, RePORTER application 10490483, Role of epigenetic alterations in the bone marrow niche to aging-related hematopoietic clonality leading to IDH mutant MDS and AML (1R56AG070121-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10490483. Licensed CC0.

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