# Modeling myelodysplasia

> **NIH NIH R01** · CINCINNATI CHILDRENS HOSP MED CTR · 2022 · $592,469

## Abstract

PROJECT SUMMARY
Myelodysplastic Syndromes (MDS) are a cancer of the hematopoietic stem cell (HSC) on the rise in the aging
population and cancer survivors. The only curative treatment for MDS is allogeneic stem cell transplantation
with marked limitations in the majority of MDS patients. As a result, standard-of-care focuses on
hypomethylating agents (HMA) azacytidine (AZA) and decitabine (DAC), which invariably result in resistance
and disease progression. There is a dire need for new therapeutics; however, there are no robust models of
MDS to accelerate preclinical testing. We have generated a breakthrough humanized xenograft-recipient
mouse model which eliminates conditioning and facilitates engraftment of primary MDS. We will validate the
model by single-cell genetic and genomic characterization of diagnostic MDS patient material before therapy
and of the same cells engrafted in humanized mice, clearly dellineating the transcriptional impact of
xenografting. Next, we will establish pharmacodynamic endpoints for AZA within the mouse model and apply
the empirically-derived dose of AZA to the model. Human MDS material will be captured for single cell
analyses post-AZA therapy from both patients and xenografts. The multi-omics comparative analyses will
incisively determine the utility of MISTRG-W41 for MDS preclinical testing, by illustrating the extent to which
AZA-affected programs in patients are similarly changed in the xenograft. This deep molecular, genotypic, and
phenotypic understanding of HMA effects on subclonal and hierarchical cellular compositions of MDS will build
the basis for comparison of novel-targeted-therapeutic agents as alternatives, concurrent, or post-HMA
therapeutic approaches.

## Key facts

- **NIH application ID:** 10320969
- **Project number:** 5R01CA253981-02
- **Recipient organization:** CINCINNATI CHILDRENS HOSP MED CTR
- **Principal Investigator:** H. LEIGHTON GRIMES
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $592,469
- **Award type:** 5
- **Project period:** 2021-01-01 → 2025-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10320969

## Citation

> US National Institutes of Health, RePORTER application 10320969, Modeling myelodysplasia (5R01CA253981-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10320969. Licensed CC0.

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