Research
The Jiang Laboratory studies the molecular mechanisms of RNA modifications in normal and cancer stem cells, how these editase enzymes are regulated in different cellular contexts, and how to target these pathways in pre-clinical models of both solid tumor and blood malignancies. The Jiang lab is pursuing these interests by studying the functions and molecular targets of RNA editing enzymes that specify normal stem cell development and maintain cancer stem cells (CSCs) in pediatric leukemia . We employ a variety of bioinformatic, molecular and cell biological tools, as well as patient samples and xenograft mouse models to address these questions surrounding human health and disease.
Project 1: Investigating the novel mechanism by which ADAR1 isoforms regulate T-ALL LIC functions.
Relapsed pediatric T-cell acute lymphoblastic leukemia (T-ALL) is often refractory to conventional therapy and is associated with a dismal survival rate of less than 25%. My lab is interested in leukemia-initiating cells (LICs) gaining enhanced self-renewal capacity and hiding themselves from host immune surveillance in T-ALL. Post-transcriptional regulation of RNA plays a critical role in important biological processes. The most common post-transcriptional modification in humans is adenosine-to-inosine (A-to-I) RNA editing mediated by ADAR1 (adenosine deaminase associated with RNA). ADAR1 is expressed as two isoforms (p150 and p110) with diverse functions in normal hematopoiesis. I discovered that >70% of T-ALL patients exhibit high expression of the ADAR1 p150 isoform, and this is associated with significantly worse clinical outcome. In contrast, ADAR1 p110 is critical only for normal hematopoietic stem cell maintenance. In addition, inhibition of ADAR1 impairs LIC survival and self-renewal and enriches cytosolic dsRNA, thus promoting an IFN-associated gene program in the tumor microenvironment (Rivera… Jiang, Cell Reports, 2024).
Project 2: Profiling human RNA editing landscape.
A unique challenge in studying ADAR1 biology is the immense number of RNA editing sites in the human transcriptome. We now have a collection of over 2 million A-to-I RNA editing events, but the majority of these sites have very low levels of RNA editing and have no relevant functional roles. Thus, an important question is which RNA editing events have critical functional and clinical implications. The lab will look at the largest T-ALL cohorts (> 1,000 epitranscriptome profiles) and perform correlation analyses to determine associations between RNA editing sites and patient survival/relapse and to identify recurrent RNA editing events that predict poor outcome. Combining bioinformatic expertise and novel molecular detection methods, we hope to uncover for the complete A-to-I RNA editing landscape in T-ALL and identify distinct and novel RNA editing modifications in patient survival, risk stratification, and treatment outcome.
Project 3: Targeting malignant RNA editing in LICs
Although an attractive therapeutic target in cancer and autoimmune diseases, no agents directly inhibiting ADAR1 have successfully advanced to the clinic. We argue that directly targeting the ADAR1 p150 isoform that is activated in LICs is the most effective approach in eliminating LICs while avoiding toxicity to hematopoietic stem cells. We will apply a novel antisense oligonucleotide (ASO) to directly target ADAR1 p150 or p110 mRNA and examine the drug efficacy in eradicating T-ALL LICs.