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Assessing the Interplay Between Inflammatory Signaling and Epigenetic Dysregulation in Age-associated Clonal Hematopoiesis and Leukemia Initiation

Award Number: U01AG077925
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/15/2021
PERIOD OF PERFORMANCE END DATE: 06/30/2027

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Assessing the Interplay Between Inflammatory Signaling and Epigenetic Dysregulation in Age-associated Clonal Hematopoiesis and Leukemia Initiation - PROJECT SUMMARY/ABSTRACT Age is one of the most clearly defined risk factors for cancer. As the incidence of cancer increases with age, rising more rapidly beginning in mid-life (ages 45-64 years), cancer can be considered an age-related disease. Recent studies have identified age-dependent somatic mutations, including alleles with a role in cancer initiation, in a spectrum of human tissues. In the hematopoietic system this is termed clonal hematopoiesis (CH) and is most commonly caused by mutations in the epigenetic regulators DNMT3A, TET2, and ASXL1 within the hematopoietic stem and progenitor cell (HSPC) compartment. How the aging process promotes clonal selection, expansion, and transformation from CH to acute myeloid leukemia (AML) is poorly understood. The long-term goal of this research is to understand the mechanisms by which aging promotes transformation causing hematologic malignancies. The overall objective of this proposal is to elucidate the mechanisms by which increased inflammation observed during aging promotes expansion of CH-mutant HSPCs, and the extent to which this fitness advantage is provided by altered epigenetic regulation occurring as a direct consequence of CH mutations. Preliminary data show that CH-mutant HSPCs have a more potent selective advantage and undergo more rapid malignant transformation in aged compared to young mice. Mechanistically, increased inflammation in aged mice is a driver of this phenotype and epigenetic alterations are found to accumulate in CH-mutant HSPCs with aging. These data support the central hypothesis that aging-associated inflammation is a selective pressure favoring CH-mutant HSPC expansion and malignant transformation, and that clonal expansion, epigenetic alterations, and risk of transformation caused by CH mutations are dependent upon sustained CH-mutant allele expression. This project will use cellular and molecular biological approaches in aged mice integrated with studies using primary human CH samples to achieve the following specific aims: AIM 1. Determine the extent to which clonal hematopoietic expansion and leukemic transformation in the aging context is due to inflammation; and AIM 2. Determine the mechanisms by which, and extent to which, reversion of a CH mutation during aging alters clonal evolution and risk of leukemia initiation. The proposed research is conceptually innovative because it is the first to determine how inflammation and epigenetic dysregulation conspire during the aging process to expand, evolve and transform CH-mutant clones. The proposed research is technically innovative as it incorporates novel co-culture systems and therapeutic studies to assess key inflammatory drivers, as well as a novel murine model with CH-mutant induction and reversion capabilities to investigate CH mutant allele dependencies in clonal expansion, epigenetic alterations, and leukemic transformation. This study is significant because understanding the mechanisms by which aging contributes to clonal expansion and transformation will provide insights into effective therapeutic strategies targeting clonal evolution, attenuate pathophysiology promoted by clonal expansion, and intercept malignant transformation.


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 = $0 )
2026	2025	JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Cancer Biology Research	000	5	2/23/2026	NON-COMPETING CONTINUATION	$0
2026	2025	JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Cancer Biology Research	001	5	4/2/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $509,734 )
2025	2025	JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Cancer Biology Research	002	5	7/31/2025	NON-COMPETING CONTINUATION	$509,734
2025	2024	JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Aging Research	001	4	6/26/2025	OTHER REVISION	$0
2025	2024	JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Aging Research	000	4	5/5/2025	TERMINATION	$0
														Subtotal = $509,734

Issue Date FY: 2024 ( Subtotal = $825,844 )
2024	2024	JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Cancer Biology Research	001	4	5/24/2024	NON-COMPETING CONTINUATION	$10,185
2024	2024	JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Cancer Biology Research	003	4	8/23/2024	SUPPLEMENT FOR EXPANSION	$197,925
2024	2024	JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Aging Research	002	4	6/28/2024	SUPPLEMENT FOR EXPANSION	$104,865
2024	2024	JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Cancer Biology Research	000	4	5/17/2024	NON-COMPETING CONTINUATION	$512,869
														Subtotal = $825,844

Issue Date FY: 2023 ( Subtotal = $515,538 )
2023	2023	JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Cancer Biology Research	000	3	8/14/2023	NON-COMPETING CONTINUATION	$515,538
														Subtotal = $515,538

Issue Date FY: 2022 ( Subtotal = $518,079 )
2022	2022	THE JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Cancer Biology Research	000	2	7/5/2022	NON-COMPETING CONTINUATION	$518,079
														Subtotal = $518,079

Issue Date FY: 2021 ( Subtotal = $538,000 )
2021	2021	THE JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Cancer Biology Research	000	1	9/13/2021	NEW	$538,000
														Subtotal = $538,000

Grand Total All Awards = $2,907,195

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Assessing the Interplay Between Inflammatory Signaling and Epigenetic Dysregulation in Age-associated Clonal Hematopoiesis and Leukemia Initiation

Award Number: U01AG077925

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

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

PERIOD OF PERFORMANCE START DATE: 09/15/2021

PERIOD OF PERFORMANCE END DATE: 06/30/2027

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