Grant Details
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 |
Abstract
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.
Publications
Malignant A-to-I RNA editing by ADAR1 drives T cell acute lymphoblastic leukemia relapse via attenuating dsRNA sensing.
Authors: Rivera M.
, Zhang H.
, Pham J.
, Isquith J.
, Zhou Q.J.
, Balaian L.
, Sasik R.
, Enlund S.
, Mark A.
, Ma W.
, et al.
.
Source: Cell Reports, 2024-02-27 00:00:00.0; 43(2), p. 113704.
EPub date: 2024-01-23 00:00:00.0.
PMID: 38265938
Related Citations