# Cellular and Molecular mechanisms of ATRA inhibition of osteoblast-induced MDS development

> **NIH NIH R01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2022 · $331,666

## Abstract

ABSTRACT
Osteoblasts are critical components of the hematopoietic stem cell (HSC) niche that regulate hematopoiesis.
More recently, they have emerged as critical regulators of the development of hematological myeloid
malignancies. We showed that a single activating mutation in -catenin signaling in osteoblasts is
sufficient to lead to the development of MDS, eventuall progressing to AML in mice. The disease is
transplantable and characterized by clonal evolution at the cytogenetic level. Activated -catenin signaling is
present in osteoblasts of 38% of MDS patients suggesting that this pathway may sustain dysplastic
hematopoiesis and progression to MDS and AML in humans. Our initial observations support this indication
and further suggest a novel means for treating this particular population of patients. In search of a potential
FDA-approved compound with the ability to inhibit -catenin signaling we came across all-trans-retinoic acid
(ATRA). ATRA is used in the treatment of acute promyelocytic leukemia where its mechanism of action relies
on its ability to dissociate the NCOR-HDACL complex from RAR and allow DNA transcription and
differentiation of the immature leukemic promyelocytes into mature granulocytes. However, reports from in vitro
studies indicate that ATRA has another function: it inhibits -catenin functions. We have found that inhibition of
-catenin signaling in 14 MDS/ patients with active -catenin in their osteoblasts with ATRA improved their
hematologic phenotype, stabilized disease status and inhibited -catenin activity. It also treated MDS and
prevented disease transformation in MDS mice expressing constitutive active -catenin in osteoblasts. Based
on these observations, we hypothesize that interrupting -catenin signaling in osteoblasts of MDS mouse
models and MDS patients with active -catenin in their osteoblasts by pharmacological means will
improve disease outcome. This may be achieved with ATRA, which may find a new use specifically in the
treatment of the portion of MDS patients with activated -catenin in their osteoblasts. To test this hypothesis
we will examine whether ATRA inhibits -catenin-induced MDS in mouse models of activated -catenin in
osteoblasts; and whether this inhibition is independent of actions on HSCs. We will also dissect the molecular
mechanism of -catenin inhibition by ATRA; and, verify the significance and specificity of ATRA inhibition in
cytogenetically different types of human MDS with activated -catenin in osteoblasts in vitro and in xenograft
models we developed to examine interactions between human MDS and stromal cells.

## Key facts

- **NIH application ID:** 10348733
- **Project number:** 5R01AR077152-02
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** STAVROULA KOUSTENI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $331,666
- **Award type:** 5
- **Project period:** 2021-02-15 → 2025-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10348733

## Citation

> US National Institutes of Health, RePORTER application 10348733, Cellular and Molecular mechanisms of ATRA inhibition of osteoblast-induced MDS development (5R01AR077152-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10348733. Licensed CC0.

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