# Characterization of the Role of ADAR1 in Oncogenic Transformation of Progenitors

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2021 · $354,563

## Abstract

Title: Characterization of the Role of ADAR1 in Oncogenic Transformation of Progenitors
Project Summary
Our overall goal is to define the role of ADAR1 in the oncogenic transformation of pre-leukemic progenitors in
myeloproliferative neoplasms (MPNs) into self-renewing leukemia stem cells (LSCs). Recent research
suggests that ADAR1-mediated RNA editing is an essential driver of human cancer progression. Though
many RNA editing sites have been identified, the functional relevance of ADAR1-mediated RNA editing,
especially in primary patient samples, is still unresolved. This study represents a unique opportunity to
understand the consequences of malignant RNA editing in cancer stem cells that drive cancer progression
and therapeutic resistance. Inflammatory cytokine driven activation of ADAR1 has been implicated in
malignant reprogramming of progenitors into self-renewing cancer stem cells in a broad array of
malignancies. Previously, we showed that ADAR1 enhances self-renewal of pre-leukemic progenitors in
chronic myeloid leukemia (CML), in part as a result of A-to-I editing induced missplicing of GSK3β, which
prevents degradation of the self-renewal agonist, β-catenin. More recently, ADAR1 has been shown to play a
role in microRNA biogenesis and specifically impairs let-7 family microRNA production. Notably, ADAR1 is
also upregulated during progression from myelofibrosis (MF) to secondary acute myeloid leukemia (sAML).
In this grant, we will first examine if ADAR1-mediated RNA editing can alter self-renewal capacity, survival,
and cell cycle in primary patient progenitors and normal progenitors following lentiviral transduction with MPN
oncogenes. Given that >90% of A-to-I editing events occur in the context of primate-specific Alu elements,
the necessity of Alu sequences for ADAR1 function will be assessed using both human and mouse
progenitors. Secondly, the impact of RNA editing on let-7 microRNA biogenesis and degradation will be
determined. Lastly, we discovered that ADAR1 edits APOBEC3 cytidine deaminase, which introduces C-to-T
mutations in a broad array of malignancies. Moreover, multiple A-to-I editing sites occur in intronic, exonic, as
well as protein coding regions of APOBEC3D and 3G, suggesting that ADAR1 might regulate APOBEC
expression and protein function. Thus, we aim to decipher the role of ADAR1 in deregulation of APOBEC3s
and introduction of DNA hypermutation patterns during evolution of pre-leukemic progenitors into leukemia
stem cells. In addition to vastly expanding our knowledge of A-to-I editing function in progenitor cell
maintenance, this research program will inform the development of malignant ADAR1 editase detection and
inhibition strategies that may help to prevent progression of MPNs to acute myeloid leukemia.

## Key facts

- **NIH application ID:** 10056196
- **Project number:** 5R01CA205944-05
- **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:** 2021
- **Award amount:** $354,563
- **Award type:** 5
- **Project period:** 2016-12-08 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10056196

## Citation

> US National Institutes of Health, RePORTER application 10056196, Characterization of the Role of ADAR1 in Oncogenic Transformation of Progenitors (5R01CA205944-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10056196. Licensed CC0.

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