# Defining malignant hematopoiesis via single-cell multi-omics

> **NIH NIH DP5** · WEILL MEDICAL COLL OF CORNELL UNIV · 2024 · $423,750

## Abstract

PROJECT SUMMARY / ABSTRACT
Clonal blood differentiation through the acquisition of somatic mutations result in abnormal accumulation of
blood components and clinically manifest as myeloid disorders. The study of how these somatic mutations
perturb the differentiation trajectories in human hematopoiesis is often challenged by the admixture of normal
hematopoietic cells with the neoplastic cells that cannot be distinguished by cell surface markers. To
overcome this limitation, we developed a novel single-cell multi-omics Genotyping of Transcriptomes (GoT)
platform that directly links somatic genotypes with transcriptomes of thousands of single cells. Thus, GoT
enabled the comparison of mutant and wildtype cells within the same sample in the context of progenitor
identities, thereby turning the co-mingling of mutant and wildtype hematopoiesis from a limitation to an
advantage. As proof of principle, GoT was applied to CD34+ progenitor cells from patients with calreticulin-
mutated myeloproliferative neoplasms (MPN), revealing key pathways that were aberrantly activated in the
mutant cells, such as a robust unfolded protein response in the megakaryocytic progenitors, on the one
way, and NF-KB pathway in stem cell-enriched populations, on the other. Overall, GoT revealed that the
transcriptional impact of calreticulin mutations is highly variable as a function of progenitor identity – which
bears significant implications for therapy by enabling the discovery of targetable pathways specific to the
earliest stem cells. Thus, to demonstrate the cell identity-dependency across other key driver mutations, as
a fundamental concept in myeloid disorders, I will apply GoT to thrombopoietin receptor-mutated progenitor
cells and to clonally-diverse cells from MPN samples (Aim 1). Next, in order to define cell extrinsic
determinants of somatic mutation impact, I will determine the immune niche interactions with calreticulin-mutant
and wildtype progenitor cells, as well as the impact of immunomodulatory therapy on these interactions (Aim
2). Finally, I will test the hypothesis that the cell’s epigenome precedes the cell identity-dependency of
somatic mutation effects, by developing and applying a novel single-cell platform that integrates somatic
genotyping with chromatin accessibility states of progenitor cells (Aim 3). Thus, I will define the genetic,
epigenetic, transcriptional and environmental factors that culminate in the clinical output of somatic mutations
in human hematopoiesis. These studies will, therefore, unveil not only fundamental concepts in clonal
hematopoietic differentiation but also specific targets for therapeutic intervention.

## Key facts

- **NIH application ID:** 10912515
- **Project number:** 5DP5OD029619-05
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Seung Ha Nam
- **Activity code:** DP5 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $423,750
- **Award type:** 5
- **Project period:** 2020-09-15 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10912515

## Citation

> US National Institutes of Health, RePORTER application 10912515, Defining malignant hematopoiesis via single-cell multi-omics (5DP5OD029619-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10912515. Licensed CC0.

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