Friday, June 27, 2025 6/27/2025

The impact of reduction of cellular senescence on age-related epigenetic heterogeneity

Award Number: U01CA271830
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2024
PERIOD OF PERFORMANCE END DATE: 08/31/2026

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The impact of reduction of cellular senescence on age-related epigenetic heterogeneity - PROJECT SUMMARY Acute myeloid leukemia (AML) occurs mostly in adults 65 years and older and is associated with age-related clonal hematopoiesis (CH). This condition that results from the clonal expansion of mutationally-marked hematopoietic stem and progenitor cells (HSPC). These HSPC expansions often feature somatic mutations in leukemia-associated genes such as the epigenetic regulator TET2. TET2-mutant CH is a risk factor for AML, and CH progression to AML is promoted by acquiring cooperating mutations such as constitutively active FLT3ITD. Yet, it is unclear how aging and TET2 mutation interact to drive the evolution of CH to leukemia. We seek to reveal the epigenetic mechanisms for how CH evolves to leukemia in an aging microenvironment, laying the foundation for therapeutic strategies to block this evolution and prevent leukemia in the aging US population. To this end, we will leverage our team's complementary expertise in intra-tumor heterogeneity and computational epigenomics; aging, cancer evolution, and leukemogenesis; inflammation and hematopoietic stem cell (HSC) biology; and mouse HSC proliferation and functional heterogeneity. Our preliminary results in mice show that HSPC epigenetic heterogeneity increases in old age. This process occurs in an aged bone marrow (BM) microenvironment characterized by inflammation and altered HSPC support. The rise of epigenetic and transcriptomic heterogeneity in HSC with Tet2 mutation (Tet2MT) and Flt3ITD precedes leukemic transformation. We hypothesize that aging and TET2 mutation cooperatively enhance epigenetic heterogeneity and evolvability of HSPC, thus contributing to clonal expansion and leukemogenesis. In Aim 1, we will determine the combined impact of aging and Tet2MT on epigenetic heterogeneity and gene regulation in HSPC by examining the somatic epigenomic landscape of Tet2MT HSPC from young (2-3 months) and old (22 months) mice, including single-cell (sc) transcriptomes by scRNA-seq, open-chromatin profiles by snATAC-seq, and DNA methylomes by RRBS. We expect to define epigenetic configurations in old Tet2MT HSPC associated with genes in self-renewal, quiescence, and responses to inflammation and stress. In Aim 2, we will define epigenetic configurations of Tet2MT HSPC that are adaptive in the aged context. We will transplant genetically barcoded HSPC into young or old mice and assess subclone expansion/contraction to determine if an age-dependent selection is for all Tet2MT HSPC or only a subset. We will use scRNA-seq and snATAC-seq to define molecular signatures and epigenetic heterogeneity of barcoded HSPC that are positively selected in the aged context. In Aim 3, we will define the epigenetic configurations of Tet2MT HSPC that are permissive to Flt3ITD-induced transformation in the aged context. We will transduce the Flt3ITD gene into young or aged Tet2MT or wild-type HSC and then transplant these genetically barcoded cells into young or old host mice. We will assess the epigenetic profiles of the selected HSPC by scRNA-seq and scATAC-seq of their identified progeny. We expect our findings will shift the paradigm for how epigenetic plasticity promotes somatic evolution and leads to cancer initiation in aging individuals.


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: 2025 ( Subtotal = $0 )
2025	2024	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90033	LOS ANGELES	USA	Cancer Biology Research	001	4	3/17/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$170,501
2025	2023	JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Cancer Biology Research	000	3	3/17/2025	SUPPLEMENT FOR EXPANSION	-$170,501
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $374,770 )
2024	2024	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90033	LOS ANGELES	USA	Cancer Biology Research	001	4	9/5/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$374,770
2024	2023	JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Cancer Biology Research	000	3	8/26/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $374,770

Issue Date FY: 2023 ( Subtotal = $573,802 )
2023	2023	JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Cancer Biology Research	002	3	8/14/2023	SUPPLEMENT FOR EXPANSION	$201,295
2023	2023	JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Cancer Biology Research	001	3	8/11/2023	NON-COMPETING CONTINUATION	$372,507
2023	2022	JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Cancer Biology Research	000	2	7/12/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $573,802

Issue Date FY: 2022 ( Subtotal = $372,507 )
2022	2022	THE JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Cancer Biology Research	000	2	9/7/2022	NON-COMPETING CONTINUATION	$372,507
														Subtotal = $372,507

Issue Date FY: 2021 ( Subtotal = $423,109 )
2021	2021	THE JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Cancer Biology Research	000	1	9/23/2021	NEW	$423,109
														Subtotal = $423,109

Grand Total All Awards = $1,744,188

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The impact of reduction of cellular senescence on age-related epigenetic heterogeneity

Award Number: U01CA271830

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

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

PERIOD OF PERFORMANCE START DATE: 09/01/2024

PERIOD OF PERFORMANCE END DATE: 08/31/2026

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