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4147 Malignant a-to-I RNA Editing By ADAR1 Drives T-Cell Acute Lymphoblastic Leukemia Relapse Via Attenuating dsRNA Sensing

Program: Oral and Poster Abstracts
Session: 603. Lymphoid Oncogenesis: Basic: Poster III
Hematology Disease Topics & Pathways:
Research, Fundamental Science, Lymphoid Leukemias, ALL, Diseases, immune mechanism, Lymphoid Malignancies, Biological Processes, molecular biology
Monday, December 11, 2023, 6:00 PM-8:00 PM

Maria D Rivera, MS1*, Jessica Pham2*, Jane Isquith, BS, MS1*, Haoran Zhang, BS1*, Jenny Zhou2*, Roman Sasik1*, Adam Mark3*, Wenxue Ma, MD, PhD2*, Frida Holm, PhD4*, Kathleen Fisch3*, Dennis John Kuo, MD, MS5*, Catriona Jamieson, MD, PhD6 and Qingfei Jiang, PhD7

1University of California, San Diego, La Jolla, CA
2University of California San Diego, La Jolla, CA
3Center for Computational Biology and Bioinformatics, UCSD, La Jolla, CA
4Karolinska Institutet, Solna, Sweden
5Rady Children's Hospital, University of California San Diego, San Diego, CA
6Division of Regenerative Medicine, Department of Medicine, and Sanford Stem Cell Institute, UCSD, La Jolla, CA
7UCSD, La Jolla, CA

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy that frequently occurs in children, adolescents, and young adults. Approximately 10-20% of T-ALL patients will experience relapse months or years following remission and will often become refractory to further treatments. The survival of relapsed/refractory patients is very poor, with an overall survival rate of less than a 25% overall survival rate. Relapsed patients often have enriched pools of leukemia initiating cells (LICs) with enhanced pro-survival and self-renewal capacity, suggesting a potential vulnerable population for effective targeted therapies with less toxicity.

An emerging research topic in LIC biology is the identification of RNA modifying enzymes that are important for LIC self-renewal and survival. ADAR1 enzymes catalyze the transition of adenosine (A) to inosine (I) in precursor double-stranded RNA (dsRNA). Epitranscriptomic A-to-I RNA editing events are widespread in the cancer transcriptome and are critical for the transition from pre-leukemic cells to fully functional LICs. Compared to myeloid leukemia, the role of ADAR1 in lymphoid progenitor maintenance and malignant transformation is not well understood.

A-to-I RNA editing has a wide range of effects on RNA biology including gene expression, splicing, RNA degradation and translation, and miRNA biogenesis and/or 3’ UTR targeting. The best documented functional roles of ADAR1 are suppression of the interferon (IFN) response and RNA editing of self-dsRNA to prevent abnormal activation of cytosolic self-dsRNA sensing. Concurrent deletion of the cytosolic dsRNA sensors melanoma differentiation-associated protein 5 (MDA5) and protein kinase R (PKR) is able to completely rescue embryo death and reverse the IFN signatures. Whether editing of immunogenic dsRNA and suppression of aberrant dsRNA sensing pathway could enhance LIC self-renewal capacities is an important question that has not been extensively addressed.

In this study, we applied bioinformatic analysis on a large cohort of T-ALL samples to examine the function of ADAR1 in the context of T-ALL LIC maintenance. We found that ADAR1 is highly expressed in ~70% of all T-ALL patients and particularly within the LIC compartment. A thorough comparison of the A-to-I RNA editing landscape between non-relapsed and relapsed T-ALL patient cohorts revealed hyper-editing is associated with both increased risk of relapse and leukemia-associated mortality. A total of 338 under-edited and 1,472 over-edited sites were found in relapsed patients compared to non-relapsed samples. However, there was very little difference in ADAR1 expression and the overall A-to-I RNA editing levels, among various molecular subtypes of T-ALL, suggesting malignant A-to-I RNA editing is a common attribute of relapsed T-ALL regardless of the genetic mutation status.

We also performed functional study in a three-dimensional human thymic organoid system and a T-ALL patient-derived xenograft (PDX) model. Depletion of ADAR1 showed striking effects in LIC survival and self-renewal with 50-90% reduction in leukemia growth. Mechanistically, we revealed complex dsRNA regulatory mechanisms of ADAR1 by directing hyper-editing of immunogenic dsRNA and retains unedited nuclear dsRNA to avoid detection by the innate immune sensor MDA5. Interesting, the dependency on ADAR1-MDA5 axis various among patients depending on the cell intrinsic level of MDA5. Collectively, our results show that ADAR1 functions as a self-renewal factor that limits the sensing of endogenous dsRNA. Thus, targeting ADAR1 presents a safe and effective therapeutic strategy for eliminating T-ALL LICs.

Disclosures: No relevant conflicts of interest to declare.

*signifies non-member of ASH