# Defining the Niche-dependent Role of RNA Editing in Aged and MDS Hematopoietic Stem and Progenitor Cell Dysfunction

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2020 · $354,469

## Abstract

Title Defining the Niche-dependent Role of RNA Editing in Aged and MDS Hematopoietic Stem and
Progenitor Cell Dysfunction
Project Summary
 During aging, impaired hematopoietic stem and progenitor cell (HSPC) maintenance induced by
clonal DNA mutations as well as niche-driven RNA processing deregulation can set the stage for
myelodysplastic syndrome (MDS) initiation. Recently, increased adenosine deaminase associated with
RNA1 (ADAR1)-mediated A-to-I editing was shown by our group and other research teams to
contribute to therapeutic resistance in a broad array of malignancies. Also, we discovered that
lentivirally enforced ADAR1 expression in HSPC enhanced myeloid differentiation commensurate with
upregulation of PU.1 and reduced dormancy. Whole transcriptome RNA sequencing (RNA-seq)
analysis demonstrated that inflammatory cytokine signaling pathways and RNA editing increased
during normal aged HSPC evolution to MDS. Thus, we hypothesized that niche dependent activation
of RNA editing by ADAR1 provides a competitive advantage for MDS over normal HSPCs. The majority
of ADAR1 mediated adenosine-to-inosine (A-to-I) RNA editing events in humans occur within double-
stranded RNA (dsRNA) loops created by primate-specific Alu sequences, which comprise 10 percent of
the human genome, thereby underscoring that important ADAR1 functional differences exist between
human HSPCs compared with their murine counterparts. However, the limited research effort aimed at
deciphering the role of ADAR1-mediated RNA editing in HSPC maintenance has been performed
primarily in mouse models rather than highly purified human HSPCs. Because ADAR1 is activated by
inflammatory cytokines that accelerate aging and MDS initiation, our main goal is to define the niche-
dependent role of RNA editing on human HSPC cell fate and cell cycle regulation during aging and
MDS initiation. We will first determine the RNA editing profile by whole transcriptome and single cell
RNA-seq, RESSqPCR and lentiviral RNA editing reporters. The functional role of ADAR1 in HSPC
aging and MDS initiation will be examined in stromal co-cultures with or without addition of
inflammatory cytokines, FUCCI2BL cell cycle reporters, and humanized aged HSC and MDS
immunocompromised mouse models. We will also examine the effect of RNA editing on APOBEC3
family of DNA deaminase function during MDS initiation. The proposed study is uniquely responsive to
PAS-13-033: Stimulating Hematology Investigation: New Endeavors (SHINE) because it will
identify the role of ADAR1-mediated regulatory mRNA and miRNA editing in HSPC myeloid lineage
commitment and cell cycle deregulation during age-dependent MDS initiation in the inflammatory bone
marrow niche. The ultimate goal of this study is to determine the biological, diagnostic and prognostic
significance of ADAR1-mediated RNA editing in HSPC aging compared with MDS initiation.

## Key facts

- **NIH application ID:** 10000133
- **Project number:** 5R01DK114468-04
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Catriona Helen Macleod Jamieson
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $354,469
- **Award type:** 5
- **Project period:** 2017-08-20 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10000133

## Citation

> US National Institutes of Health, RePORTER application 10000133, Defining the Niche-dependent Role of RNA Editing in Aged and MDS Hematopoietic Stem and Progenitor Cell Dysfunction (5R01DK114468-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10000133. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*