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Molecular mechanism underlying clonal expansion of hematopoietic stem cells

Award Number: R01HL150624
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/15/2019
PERIOD OF PERFORMANCE END DATE: 03/31/2028

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Molecular mechanism underlying clonal expansion of hematopoietic stem cells - PROJECT SUMMARY Clonal hematopoiesis of indeterminate potential (CHIP) increases with age and occurs when a single mutant hematopoietic stem cell (HSC) contributes to a significant clonal proportion of mature blood lineages. CHIP is associated with increased risks of developing hematological malignancies. TP53 mutations rank in the top 5 among mutations identified in CHIP and clinical studies showed that expansion of TP53 mutated HSCs with age predisposes individuals with CHIP to myeloid neoplasms such as myelodysplastic syndromes (MDS). During the previous funding period, we found that mutant p53 utilizes a cell intrinsic mechanism to drive clonal hematopoiesis through enhancing EZH2 activity and increasing H3K27me3 in HSCs. However, there is a significant gap in knowledge regarding the mechanisms by which extrinsic factors drive TP53 mutant clonal hematopoiesis. In the competitive renewal, we will focus on determining the impact of inflammatory stress on TP53 mutant clonal hematopoiesis and developing novel strategies for preventing the progression of clonal hematopoiesis to MDS. Infection activates inflammatory response and induces chronic inflammation. We discovered that bacterial infection confers a competitive advantage to p53 mutant hematopoietic stem and progenitor cells (HSPCs) via activating the NLRP1 inflammasome and increasing the secretion of proinflammatory cytokines. Furthermore, we found that some p53 mutant mice developed MDS with age and that there are increased levels of IL-1β and IL-6 in the BM of aged p53 mutant mice. We hypothesize that mutant p53 enhances inflammatory stress via activating the NLRP1 inflammasome and increasing the secretion of proinflammatory cytokines, thereby generating a chronic inflammatory microenvironment that inhibits wild type (WT) hematopoietic stem and progenitor cell (HSPC) fitness in a paracrine fashion. We further speculate that reducing chronic inflammation will prevent or delay the progression of TP53 mutant clonal hematopoiesis to myelodysplastic syndromes (MDS). To test the hypothesis, we will determine the mechanisms by which inflammatory stress drives TP53 mutant clonal hematopoiesis. We will develop novel strategies that block TP53 mutant clonal hematopoiesis from progression to MDS. Delineating the impact of inflammatory stress on p53 mutant HSPC expansion will fill a significant knowledge gap regarding the mechanisms by which extrinsic factors drive TP53 mutant clonal hematopoiesis and promote the development of MDS.


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 = $664,714 )
2026	2026	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Blood Diseases and Resources Research	000	7	3/26/2026	NON-COMPETING CONTINUATION	$664,714
														Subtotal = $664,714

Issue Date FY: 2025 ( Subtotal = $772,005 )
2025	2025	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Blood Diseases and Resources Research	002	6	9/22/2025	SUPPLEMENT FOR EXPANSION	$93,727
2025	2025	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Blood Diseases and Resources Research	001	6	7/23/2025	NON-COMPETING CONTINUATION	$678,278
2025	2022	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Blood Diseases and Resources Research	000	4	3/18/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $772,005

Issue Date FY: 2024 ( Subtotal = $729,693 )
2024	2024	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Blood Diseases and Resources Research	003	5	8/28/2024	SUPPLEMENT FOR EXPANSION	$51,415
2024	2024	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Blood Diseases and Resources Research	001	5	3/25/2024	COMPETING CONTINUATION	$610,451
2024	2024	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Blood Diseases and Resources Research	002	5	6/14/2024	COMPETING CONTINUATION	$67,827
2024	2022	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Blood Diseases and Resources Research	000	4	3/20/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $729,693

Issue Date FY: 2022 ( Subtotal = $393,750 )
2022	2022	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Blood Diseases and Resources Research	000	4	6/10/2022	NON-COMPETING CONTINUATION	$393,750
														Subtotal = $393,750

Issue Date FY: 2021 ( Subtotal = $393,384 )
2021	2021	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Blood Diseases and Resources Research	001	3	8/13/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$393,384
2021	2021	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Blood Diseases and Resources Research	003	3	8/24/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$80,105
2021	2020	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Blood Diseases and Resources Research	000	2	8/11/2021	NON-COMPETING CONTINUATION	$0
2021	2020	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Blood Diseases and Resources Research	002	2	8/24/2021	NON-COMPETING CONTINUATION	-$80,105
														Subtotal = $393,384

Issue Date FY: 2020 ( Subtotal = $393,750 )
2020	2020	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Blood Diseases and Resources Research	000	2	6/11/2020	NON-COMPETING CONTINUATION	$393,750
														Subtotal = $393,750

Issue Date FY: 2019 ( Subtotal = $393,750 )
2019	2019	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Blood Diseases and Resources Research	000	1	7/9/2019	NEW	$393,750
														Subtotal = $393,750

Grand Total All Awards = $3,741,046

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Molecular mechanism underlying clonal expansion of hematopoietic stem cells

Award Number: R01HL150624

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/15/2019

PERIOD OF PERFORMANCE END DATE: 03/31/2028

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