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Mechanisms underlying increased risk of hematological malignancy in sickle cell disease.

Award Number: R21CA299166
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2025
PERIOD OF PERFORMANCE END DATE: 03/31/2027

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Mechanisms underlying increased risk of hematological malignancy in sickle cell disease. - PROJECT SUMMARY/ABSTRACT Sickle cell disease (SCD) affects millions globally and results in recurrent vascular occlusions, chronic organ damage and early death. While childhood mortality is reduced and patients are surviving to adulthood with current therapies, an increased risk of hematological malignancy (HM) in SCD is becoming evident. Risk of HM is higher following gene therapy. Gene therapy involves hematopoietic stem cell transplant (HCT) of gene- modified autologous/sickle hematopoietic stem and progenitor cells (HSPC), and has had remarkable success and FDA approval. A similar high risk is observed in allogeneic-HCT SCD patients with suboptimal engraftment. However, the specific pathobiology that predisposes to increased HM is unknown, and necessary to address, since curative therapies (gene therapy and HCT) are on the forefront. We hypothesize that increased oxidative stress induced DNA damage results in HSPC clones with deleterious mutations; these clones amplify due to persistent HSPC replicative stress from SCD, and when the replicative stress is further magnified in gene therapy, where autologous gene-modified HSPC have to regenerate to reconstitute the entire hematopoiesis following myeloablative conditioning. We will: (1) Perform gain and loss of function experiments to increase or reduce the oxidative stress-induced DNA damage to HSPC, and study the development of clonal hematopoiesis and HM in SCD mice versus their normal counterparts. (2) Impose HCT-mediated regenerative stress on autologous young and old HSPC and assess whether development of HM occurs de novo, or from existing clones with deleterious mutations in putative oncogenes by high-depth next generation sequencing. Modeling the increased risk of HM in SCD will help identify underlying mechanisms, which can then be targeted to mitigate this risk.


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 = $187,584 )
2026	2026	CHILDRENS HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Cancer Treatment Research	000	2	4/7/2026	NON-COMPETING CONTINUATION	$187,584
														Subtotal = $187,584

Issue Date FY: 2025 ( Subtotal = $225,101 )
2025	2025	CHILDRENS HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Cancer Treatment Research	000	1	4/1/2025	NEW	$225,101
														Subtotal = $225,101

Grand Total All Awards = $412,685

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Mechanisms underlying increased risk of hematological malignancy in sickle cell disease.

Award Number: R21CA299166

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/01/2025

PERIOD OF PERFORMANCE END DATE: 03/31/2027

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