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Investigating the role of epitranscriptomic A-to-I RNA editing in T-cell acute lymphoblastic leukemia

Award Number: K22CA229606
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 09/01/2019
PERIOD OF PERFORMANCE END DATE: 02/28/2023

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Investigating the role of epitranscriptomic A-to-I RNA editing in T-cell acute lymphoblastic leukemia - Project Summary The ultimate goal of this proposal is to address a compelling unmet medical need to identify novel epitranscriptomic mechanisms of oncogenic transformation that will guide development of diagnostic and therapeutic strategies capable of predicting and preventing progression of T-cell acute lymphoblastic leukemia (T-ALL). Acute lymphoblastic leukemia (ALL) is the most prevalent hematological cancer in children younger than 14 years of age. Despite progress in intensive chemotherapy, 20-25% of pediatric and over 50% of adult patients show resistance to therapy and relapse. Widespread aberrant epitranscriptomic ADAR1-mediated adenosine-to-inosine (A-to-I) RNA editing has been associated with clinical characteristics of several cancer types and generation of leukemia initiating cells (LICs) with enhanced pro-survival and self-renewal capacity. Interestingly, activation of janus kinase (JAK)/STAT signaling by interleukin-7 (IL-7) drives expression of key stem cell regulatory pathway ADAR1-LIN28 and pro-survival factors in hematological malignancies including T-ALL. Our central hypothesis is that mutational pro-inflammatory signals, such as NOTCH and JAK/STAT signaling pathway, induce aberrant RNA editing driven by ADAR1 activation in T-ALL-initiating cells that accentuated by enhanced survival and self-renewal capacity. The three specific aims will be (1) examine if the ADAR1-mediated RNA editing promotes oncogenic transformation of normal T cell progenitor to T-ALL LICs by enhancing T-ALL LIC survival and self-renewal pathways; (2); examine whether ADAR1 activity is enhanced in T-ALL LIC cells due to NOTCH or JAK/STAT signaling pathway activation, and lastly (3) determine whether direct inhibition of ADAR1 activity by shRNA strategy impairs the survival and self-renewal impairs T-ALL LIC maintenance. This proposal will utilize established biorepository of primary T-ALL patient specimen, along with age-matched healthy control samples. In addition, lentiviral-based tools and established robust in vivo human xenograft T-ALL mouse models will be used for selective ablation of ADAR1 transcripts to thoroughly investigate the relationship between ADAR1 expression and generation of drug-resistant T- ALL-initiating LIC cells. Detailed functional and mechanistic lentiviral-directed transcript overexpression and knockdown studies will validate sensitive whole transcriptome RNA-Sequencing that correlate ADAR1 expression with LIC survival and self-renewal signaling pathway and stem cell gene expression signatures. This research strategy is uniquely integrated into my career development plan, including additional trainings in data management, basic and translational research, research ethics, and professional and leadership development. By providing a more mechanistic understanding of the role of ADAR1 in cancer, this grant will inform future RNA editase detection and inhibition strategies that may help to obviate cancer resistance and relapse.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2021	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Cancer Research Manpower	000	3	12/5/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $191,213 )
2021	2021	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Cancer Research Manpower	000	3	7/13/2021	NON-COMPETING CONTINUATION	$191,213
														Subtotal = $191,213

Issue Date FY: 2020 ( Subtotal = $191,213 )
2020	2020	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Cancer Research Manpower	000	2	7/21/2020	NON-COMPETING CONTINUATION	$191,213
														Subtotal = $191,213

Issue Date FY: 2019 ( Subtotal = $191,213 )
2019	2019	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR DEPT 621	LA JOLLA	CA	92093	SAN DIEGO	USA	Cancer Research Manpower	000	1	8/9/2019	NEW	$191,213
														Subtotal = $191,213

Grand Total All Awards = $573,639

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Investigating the role of epitranscriptomic A-to-I RNA editing in T-cell acute lymphoblastic leukemia

Award Number: K22CA229606

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 09/01/2019

PERIOD OF PERFORMANCE END DATE: 02/28/2023

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