Grant Number:	1R03CA287274-01 Interpret this number
Primary Investigator:	Jiang, Qingfei
Organization:	University Of California, San Diego
Project Title:	Profiling Epitranscriptomic Rna Editing in Pediatric Cancer
Fiscal Year:	2024

SUMMARY/ABSTRACT 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%. Thus, the development of novel therapies for relapsed T-ALL represents an urgent unmet medical need in children. Adenosine deaminase acting on RNA 1 (ADAR1) mediates the conversion of adenosine (A) to inosine (I) in the mammalian transcriptome. Malignant ADAR1 activation and over-editing was reported in extensively reported in adult cancer type. As a result, there is an intense interest to understand the mechanisms by which ADAR1-directed A-to-I RNA editing regulates gene expression, and how these editing events influence tumorigenesis. However, the global landscape of A-to-I RNA editing in pediatric cancer has not been systematically characterized. Fulfilling this knowledge gap will allow mechanistic and functional studies of these RNA editing modifications that can ultimately aid in formulating new therapeutic and preventive strategies. We discovered that 70% of T-ALL patients exhibit high expression of ADAR1, and this is associated with a significantly worse clinical outcome. Our RNA editing analysis of over 260 T-ALL patients revealed wide-spread A-to-I RNA mutations in the relapsed T-ALL cohort. Strikingly, we found that inhibiting ADAR1 impairs malignant T-ALL progenitor propogation. These discoveries need to be validated in a large cohort of T-ALL patients to further delineate the critical RNA editing “mutations” associated with relapse. The overall objective of this study is to leverage on the large sample size in Kids First Program to fully understand the heterogenous RNA editing landscape in T-ALL pathogenesis. Our central hypothesis that ADAR1 promotes unique A-to-I RNA editing changes in T-ALL which drives disease relapse and therapeutic resistance. In this proposal, we will 1) define the ADAR1-controlled A-to-I RNA editing landscape in 1,304 T-ALL patients by combining the Kids First and NCI TARGET datasets, 2) identify novel RNA editing events that predict disease outcome, and 3) compare the RNA editing landscapes in various molecular subtypes to reveal any critical link between RNA editing and genetic background. Our preliminary studies and the proposed work together will provide the first complete A-to-I RNA editing landscape in T-ALL that will be shared within the pediatric research community. In addition, we will provide new insights into the mechanisms and functions of ADAR1 in T-ALL pathogenesis and will substantially advance our understanding of the epitranscriptomic regulation in pediatric malignancies. The success of this work will reveal a comprehensive evaluation of the RNA editing network that provides advantages for leukemia expansion, and RNA hyper-editing events which may serve as an attractive therapeutic target.





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