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Principal Investigator: Qingfei Jiang
Organization: UNIVERSITY OF CALIFORNIA, SAN DIEGO
Fiscal Year: 2024
Award: $476,234
Funding agency: National Cancer Institute
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. Relapsed/refractory T-ALL is often enriched with
leukemia initiating cells (LICs), which exhibit enhanced survival and self-renewal capacity. Our long-term goal is
to identify new targets for development of less toxic and more effective therapies by eliminating this cell
population. We discovered that adenosine deaminase acting on RNA 1 (ADAR1) activation is required LIC
maintenance by directing cell-type-specific gene programs to prevent interferon activation and aberrant double-
stranded RNA (dsRNA) sensing. Approximately 70% of T-ALL patients exhibit high expression of ADAR1, and
this is associated with a significantly worse clinical outcome. Strikingly, we found that inhibiting ADAR1 impairs
malignant T-ALL progenitor prorogation. These data suggest that ADAR1 has a fundamental role in LIC self-
renewal and therapeutic resistance in T-ALL. The overall objective of this study is to dissect the mechanism
through which ADAR1 and RNA editing promote LIC self-renewal in T-ALL patients. Our central hypothesis is
that activation of ADAR1 supports T-ALL LIC maintenance by suppressing aberrant dsRNA sensing in an
isoform-specific manner. We will test this hypothesis in three independent aims: 1) Examine if ADAR1 promotes
LIC self-renewal in relapsed T-ALL by increasing RNA editing, 2) elucidate the molecular mechanism by which
ADAR1 promotes LIC activity, and 3) investigate if NOTCH1 signaling induces ADAR1 activation in T-ALL LIC.
We will directly evaluate the isoform-specific function of ADAR1 p150 and p110 isoforms in LICs within human
thymic organoids and patient-derived xenograft mouse models of T-ALL. We will use single cell RNA-sequencing
to investigate the mechanisms by which p150 and p110 isoforms regulate cellular function and gene expression
in T-ALL LICs. In Aim 2, we will perform concurrent knockdown of dsRNA sensors in combination with ADAR1
isoform knockout in LICs to determine if aberrant dsRNA sensing disrupts LIC activities in patient-derived
xenograft mouse models. Mechanistically, we will map dsRNA-containing genes suppressed by either RNA
editing or dsRNA activity of ADAR1. In Aim 3, we will use g-secretase inhibitor (GSI) and DDL1-expressing thymic
co-culture system to examine if NOTCH signaling contributes to ADAR1 activation, and if ectopic expression of
ADAR1 can bypass the need for NOTCH signaling and induces resistance to GSI inhibition. Lastly, we will
investigate if ADAR1 is a direct transcriptional target of NOTCH1. These studies will improve our understanding
of how dysregulation of ADAR1 contributes to LIC self-renewal and T-ALL progression. Furthermore, these
studies will expand our fundamental understanding of the mechanisms underlying LICs-driven malignancies and
may be broadly applicable to other cancer stem cell-driven malignancies.
Terms: <0-11 years old><Acute T Cell Leukemia><Acute T-Cell Lymphoblastic Leukemia><Acute T-Cell Lymphocytic Leukemia><Acute T-Lymphocytic Leukemia><Adenosine><Apoptosis><Apoptosis Pathway><Blood Precursor Cell><Bypass><Cancers><Cell Body><Cell Communication and Signaling><Cell Function><Cell Growth and Maintenance><Cell Maintenance><Cell Physiology><Cell Process><Cell Signaling><Cell Survival><Cell Viability><Cells><Cellular Function><Cellular Physiology><Cellular Process><Child><Child Youth><Childhood Precursor T Lymphoblastic Leukemia><Children (0-21)><Clinical><Co-culture><Cocultivation><Coculture><Coculture Techniques><Data><Deaminase><Development><Double-Stranded RNA><Drosophila Homolog of NOTCH 1><Ectopic Expression><Enzyme Gene><Enzymes><Exhibits><Future><Gene Expression><Gene Transcription><Genes><Genetic Alteration><Genetic Change><Genetic Transcription><Genetic defect><Goals><HSC regeneration><HSC self-renewal><Hematopoietic Progenitor Cells><Hematopoietic stem cells><Human><IFN><IFN activation><Impairment><Inflammation><Innate Immune Response><Inosine><Interferon Activation><Interferons><Intracellular Communication and Signaling><Isoforms><Knock-out><Knockout><Leukemic progenitor and stem cell><Ligands><Link><Maintenance><Malignant><Malignant - descriptor><Malignant Cell><Malignant Neoplasms><Malignant Tumor><Maps><Mediating><Medical><Mission><Modern Man><Molecular><Mutation><NIH><NOTCH1><NOTCH1 gene><National Institutes of Health><Non-Polyadenylated RNA><Nuclear><Oncogenic><Organoids><Outcome><PDX model><Patient derived xenograft><Patients><Play><Population><Precursor T Lymphoblastic Leukemia><Programmed Cell Death><Protein Isoforms><RNA><RNA Binding><RNA Editing><RNA Expression><RNA Gene Products><RNA bound><RNA, Messenger, Editing><Refractory><Relapse><Resistance><Ribonucleic Acid><Role><Series><Signal Induction><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Stress><Subcellular Process><Survival Rate><System><T-Cell Childhood ALL><T-Cell Childhood Acute Lymphoblastic Leukemia><T-Cell Childhood Acute Lymphocytic Leukemia><T-Cell Leukemia><T-Cell Lymphocytic Leukemia><T-Cell Pediatric ALL><T-Cell Pediatric Acute Lymphoblastic Leukemia><T-Cell Pediatric Acute Lymphocytic Leukemia><T-Cell Type Acute Leukemia><T-Lymphocytic Leukemia><T-lineage acute lymphoblastic leukemia><TAN1><Testing><Thymus><Thymus Gland><Thymus Proper><Thymus Reticuloendothelial System><Transcription><Translocation-Associated NOTCH Homolog><United States National Institutes of Health><Work><adenosine deaminase that acts on RNA><biological signal transduction><blood cell progenitor><blood progenitor><blood stem cell><blood stem cell self-renewal><blood-forming stem cell><cancer cell><cancer progenitor><cancer progenitor cells><cancer stem cell><cell type><conventional therapy><conventional treatment><curative intervention><curative therapeutic><curative therapy><curative treatments><dADAR><developmental><double-stranded RNA-specific adenosine deaminase><dsRNA><dsRNA adenosine deaminase><dsRNA-specific adenosine deaminase><effective therapy><effective treatment><experiment><experimental research><experimental study><experiments><genome mutation><hematopoietic progenitor><hematopoietic progenitor cell self-renewal><hematopoietic stem cell regeneration><hematopoietic stem cell self-renewal><hematopoietic stem progenitor cell><hemopoietic progenitor><hemopoietic stem cell><improved><inhibitor><kids><knock-down><knockdown><leukemia initiating cell><leukemic progenitor><leukemic stem cell><malignancy><malignant progenitor><malignant stem cell><mouse model><murine model><neoplasm/cancer><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><notch><notch protein><notch receptors><novel><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><patient derived xenograft model><prevent><preventing><programs><resistance to therapy><resistant><resistant to therapy><scRNA-seq><secretase><self-renew><self-renewal><sensor><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><social role><therapeutic agent development><therapeutic development><therapeutic resistance><therapy resistant><treatment resistance><youngster>