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Exploring the Impact of Base Deaminase Deregulation on Precancer Evolution

Award Number: R01CA296974
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/01/2024
PERIOD OF PERFORMANCE END DATE: 11/30/2029

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Exploring the Impact of Base Deaminase Deregulation on Precancer Evolution - PROJECT SUMMARY Recent research suggests that primate-specific APOBEC3C-mediated C-to-T DNA and ADAR1-mediated A-to- I RNA editing represent essential drivers of human cancer progression. Though many DNA and RNA editing sites have been identified, the functional relevance of APOBEC3C and ADAR1 deaminase deregulation, especially in primary patient samples, is still unresolved. By elucidating the relative roles of APOBEC3C and ADAR1 in myeloproliferative neoplasm (MPN) progression to secondary acute myeloid leukemia (sAML), this represents a unique opportunity to understand how DNA and RNA editing deregulation drive cancer stem cell generation and therapeutic resistance. While pro-inflammatory cytokine-responsive ADAR1 (adenosine deaminase acting on RNA 1) and APOBEC3 (apolipoprotein B mRNA editing enzyme, catalytic polypeptide like type 3) base deaminases restrict viral replication5 and LINE element retrotransposition, base deaminase deregulation has been linked to both genomic and epitranscriptomic (post-transcriptional modification) instability. We have shown that pro-inflammatory cytokines activate primate specific APOBEC3C-mediated cytidine to thymidine (C-to-T) deamination of DNA and ADAR1 p150 isoform-mediated adenosine to inosine (A-to-I) deamination of double-stranded RNA (dsRNA) thereby fueling transformation of pre-LSCs to LSCs in myeloproliferative neoplasms (MPN). The overall goal of this proposal is to continue our investigation of malignant deaminase activation in directing human pre-LSC evolution to sAML LSCs with the ultimate aim of informing the development of effective strategies that predict and prevent transformation to rapidly fatal sAML. We will investigate if ADAR1 shRNA knockdown reduces telomere length, TERT expression and alters the self-renewal program in pre-LSCs and LSCs in stromal co-cultures and humanized mouse models. In Aim 2, we proposed to examine the detailed mechanisms of how ADAR1 drives WNT/beta-catenin signaling in primary patient samples in stromal co-cultures and humanized mouse models as well as reporter and confocal fluorescent microscopy. Lastly, we will test if activation of both APOBEC3C and ADAR1p150 fuels pre-LSC evolution by whole genome sequencing, Tapestri single cell DNA, and proteomic sequencing platform. In addition to vastly expanding our knowledge of A-to-I editing function in progenitor cell maintenance, this research program will inform the development of malignant ADAR1 editase detection and inhibition strategies that may help to prevent progression of MPNs to acute myeloid leukemia.


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: 2026 ( Subtotal = $400,582 )
2026	2026	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Cancer Biology Research	000	2	12/10/2025	NON-COMPETING CONTINUATION	$400,582
														Subtotal = $400,582

Issue Date FY: 2025 ( Subtotal = $444,952 )
2025	2025	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Cancer Biology Research	000	1	11/27/2024	NEW	$444,952
														Subtotal = $444,952

Grand Total All Awards = $845,534

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Exploring the Impact of Base Deaminase Deregulation on Precancer Evolution

Award Number: R01CA296974

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 12/01/2024

PERIOD OF PERFORMANCE END DATE: 11/30/2029

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