# Clinical and Molecular Heterogeneity in the Myelodysplastic Syndromes

> **NIH NIH R01** · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · 2022 · $688,759

## Abstract

SUMMARY
 MDS represents a group of acquired bone marrow failure syndromes arising from hematopoietic stem cells
(HSCs). While most MDS patients experience progressive cytopenias, a significant minority (30%) will progress
to acute myeloid leukemia (AML); however, the mechanisms that determine whether patients experience
progressive cytopenias or leukemia transformation are poorly understood. While the ineffectiveness of MDS
therapies is due to their inability to effectively eliminate MDS clones and/or restore normal differentiation, it
remains unclear whether hypomethylating agents (HMAs) act on HSCs or committed progenitors to induce
hematologic improvement and/or reductions in blast count, or if HMAs act through similar or unique mechanisms
in these distinct cell populations. We and others have shown that MDS HSCs exhibit markedly different gene
expression profiles than CD34+ hematopoietic stem/progenitor cells (HSPCs) and that they are also genetically
and transcriptionally heterogeneous6-10; however, these prior studies were not designed to specifically capture
committed progenitor contributions to disease progression or therapeutic responses to HMAs. We hypothesize
that HSCs and committed progenitors from MDS patients who experience progressive cytopenias or
leukemic transformation exhibit unique transcriptional signatures prior to, and in response to, HMA
therapy. Secondarily, we hypothesize that HMAs induce unique transcriptional and functional changes
in MDS HSCs and committed progenitors, and that their ability to induce specific transcriptional
programs determines whether or not patients respond with hematologic improvements and/or blast
reductions. We propose to elucidate the transcriptional basis of HSC and committed progenitor responses from
MDS patients at the single cell level using novel full-length cDNA scRNA-seq technologies that will allow
simultaneous characterization of the transcriptome and mutational data within individual cells from paired pre-
and post-therapy samples from MDS patients with different types of disease progression and responses to HMA
therapy. We also will evaluate the clinical relevance of our findings by evaluating MDS-associated RNA features
in larger cohorts of MDS patients for whom transcriptome data and clinical outcome data are available.
Assessments of the contribution of dysregulated transcripts to MDS progression will be evaluated using mouse
models of MDS as well as primary MDS patient cells. Overall, we expect our studies to: 1) Identify the genes
and biological pathways that determine whether MDS patients will experience progressive cytopenia versus
leukemic transformation; 2) Elucidate the roles of different HSPC populations in determining clinical responses
to HMA therapy; 3) Identify novel biomarkers for prognostication of clinical outcomes and therapy responses in
MDS; 4) Provide the biological rationale for future clinical studies of novel pathway- or genetically-targeted
agents in combina...

## Key facts

- **NIH application ID:** 10370374
- **Project number:** 5R01CA249054-03
- **Recipient organization:** NEW YORK UNIVERSITY SCHOOL OF MEDICINE
- **Principal Investigator:** Christopher Edward Mason
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $688,759
- **Award type:** 5
- **Project period:** 2020-04-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10370374

## Citation

> US National Institutes of Health, RePORTER application 10370374, Clinical and Molecular Heterogeneity in the Myelodysplastic Syndromes (5R01CA249054-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10370374. Licensed CC0.

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