# Investigating the role of epitranscriptomic A-to-I RNA editing in T-cell acute lymphoblastic leukemia

> **NIH NIH K22** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2020 · $191,213

## Abstract

Project Summary
The ultimate goal of this proposal is to address a compelling unmet medical need to identify novel
epitranscriptomic mechanisms of oncogenic transformation that will guide development of diagnostic and
therapeutic strategies capable of predicting and preventing progression of T-cell acute lymphoblastic
leukemia (T-ALL). Acute lymphoblastic leukemia (ALL) is the most prevalent hematological cancer in
children younger than 14 years of age. Despite progress in intensive chemotherapy, 20-25% of pediatric
and over 50% of adult patients show resistance to therapy and relapse. Widespread aberrant
epitranscriptomic ADAR1-mediated adenosine-to-inosine (A-to-I) RNA editing has been associated with
clinical characteristics of several cancer types and generation of leukemia initiating cells (LICs) with
enhanced pro-survival and self-renewal capacity. Interestingly, activation of janus kinase (JAK)/STAT
signaling by interleukin-7 (IL-7) drives expression of key stem cell regulatory pathway ADAR1-LIN28 and
pro-survival factors in hematological malignancies including T-ALL. Our central hypothesis is that
mutational pro-inflammatory signals, such as NOTCH and JAK/STAT signaling pathway, induce aberrant
RNA editing driven by ADAR1 activation in T-ALL-initiating cells that accentuated by enhanced survival
and self-renewal capacity. The three specific aims will be (1) examine if the ADAR1-mediated RNA editing
promotes oncogenic transformation of normal T cell progenitor to T-ALL LICs by enhancing T-ALL LIC
survival and self-renewal pathways; (2); examine whether ADAR1 activity is enhanced in T-ALL LIC cells
due to NOTCH or JAK/STAT signaling pathway activation, and lastly (3) determine whether direct
inhibition of ADAR1 activity by shRNA strategy impairs the survival and self-renewal impairs T-ALL LIC
maintenance. This proposal will utilize established biorepository of primary T-ALL patient specimen,
along with age-matched healthy control samples. In addition, lentiviral-based tools and established robust
in vivo human xenograft T-ALL mouse models will be used for selective ablation of ADAR1 transcripts to
thoroughly investigate the relationship between ADAR1 expression and generation of drug-resistant T-
ALL-initiating LIC cells. Detailed functional and mechanistic lentiviral-directed transcript overexpression
and knockdown studies will validate sensitive whole transcriptome RNA-Sequencing that correlate
ADAR1 expression with LIC survival and self-renewal signaling pathway and stem cell gene expression
signatures. This research strategy is uniquely integrated into my career development plan, including
additional trainings in data management, basic and translational research, research ethics, and
professional and leadership development. By providing a more mechanistic understanding of the role of
ADAR1 in cancer, this grant will inform future RNA editase detection and inhibition strategies that may
help to obviate cancer resistance and relapse.

## Key facts

- **NIH application ID:** 9993431
- **Project number:** 5K22CA229606-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Qingfei Jiang
- **Activity code:** K22 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $191,213
- **Award type:** 5
- **Project period:** 2019-09-01 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9993431

## Citation

> US National Institutes of Health, RePORTER application 9993431, Investigating the role of epitranscriptomic A-to-I RNA editing in T-cell acute lymphoblastic leukemia (5K22CA229606-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9993431. Licensed CC0.

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