# Integrating genetic, epigenetic, and microenvironmental determinants of myeloproliferative neoplasms via single-cell multi-omics

> **NIH NIH K08** · WEILL MEDICAL COLL OF CORNELL UNIV · 2020 · $155,671

## Abstract

PROJECT SUMMARY / ABSTRACT
Research Plan: Somatic mutations in hematopoietic progenitor cells (HPCs) drive the development of chronic
blood disorders, such as CALR mutations in myeloproliferative neoplasms (MPN). In human, CALR mutations
can lead to diverging clinical presentations of essential thrombocythemia (ET) or myelofibrosis (MF).
Nevertheless, the study of the mutation impact on 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 Genotyping of Transcriptomes (GoT) platform that
directly links somatic genotypes with transcriptional profiles 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. GoT was
applied to CD34+ progenitor cells from patients with CALR-mutated ET and MF, revealing that transcriptional
impact of CALR mutations is highly variable as a function of progenitor identity. This raises the question of what
are the factors that lead to the cell identity-dependent transcriptional dysregulation by the CALR mutations?
First, we will test the hypothesis that the cell’s epigenome constrains the CALR mutation-induced transcriptional
impact and is, in turn, modified by the downstream effects of the CALR mutations (Aim 1). Novel single-cell
multi-omics that integrates the epigenome, transcriptome and mutation status will be applied to the progenitors
from primary human samples. Second, we hypothesize that the immune microenvironment may directly interact
with the mutant HPCs to further modify the somatic mutation impact (Aim 2). Thus, the progenitor-to-immune
cell interactions will be defined. We will interrogate the progenitors’ epigenome and interactions with the immune
microenvironment in ET vs. MF, to determine the distinct molecular factors that may underlie the development
of marrow fibrosis (Aims 1 and 2). Third, we will examine the impact of interferon in CALR-mutated ET to define
its perturbations on the epigenome and transcriptome of the mutant progenitor cells and their interactions with
the immune cells (Aim 3). We will examine serial samples from patients treated with interferon in the context of
their clinical response, to determine the molecular underpinnings of differential therapeutic response.
Thus, we will define cell-intrinsic determinants (e.g. cell’s epigenome) and cell-extrinsic factors (e.g. immune
microenvironment and therapy) that interact with somatic mutation impact to result in distinct cell identity-
dependent transcriptional effects and, ultimately, distinct clinical presentations and response to therapy.
Career Development Plan: Dr. Nam has outlined a 5-year career development plan to meet her goal of
becoming an independent investigator in hematopoiesis research. She has organized an advisory committee
composed not only of leade...

## Key facts

- **NIH application ID:** 9953735
- **Project number:** 1K08HL151960-01
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Seung Ha Nam
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $155,671
- **Award type:** 1
- **Project period:** 2020-04-01 → 2020-09-14

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9953735

## Citation

> US National Institutes of Health, RePORTER application 9953735, Integrating genetic, epigenetic, and microenvironmental determinants of myeloproliferative neoplasms via single-cell multi-omics (1K08HL151960-01). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/9953735. Licensed CC0.

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