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EXAMINING THE IMPACT OF DNMT3A PROTEIN REDUCTION ON NORMAL AND CLONAL HEMATOPOIESIS

Award Number: K99HL188297
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 09/01/2026
PERIOD OF PERFORMANCE END DATE: 07/31/2028

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EXAMINING THE IMPACT OF DNMT3A PROTEIN REDUCTION ON NORMAL AND CLONAL HEMATOPOIESIS - PROJECT SUMMARY AND ABSTRACT Certain somatic mutations result in the clonal expansion of mutated hematopoietic stem and progenitor cells (HSPCs). This phenomenon, called clonal hematopoiesis (CH), accelerates with age and is associated with an ~11-fold increase in the risk of hematologic disorders such as aplastic anemia (AA) and myelodysplastic syndrome (MDS), as well as chronic inflammatory diseases like cardiovascular disease, and increased all-cause mortality. DNA methyltransferase 3A (DNMT3A) plays an important role in regulating normal HSPC proliferation, and mutations in DNMT3A are some of the most common in CH. Our recent research shows that one-third of CH-related mutations in DNMT3A downregulate its protein levels through the E3 ubiquitin ligase adaptor DCAF8 in hematopoiesis, and this effect is counteracted by the deubiquitinating enzyme USP11. As a result of these mutations, the DNA MTase activity of DNMT3A is decreased in mutant hematopoietic cells. Dr. Taishi Yonezawa hypothesizes that maintaining wild-type (WT) levels of DNMT3A protein is critical for normal hematopoiesis and the disruption of DNMT3A protein function leads to CH. To address his hypothesis, he will investigate the mechanisms underlying the regulation of DNMT3A WT protein fate in hematopoiesis (K99 phase) and identify approaches to modulate CH caused by unstable DNMT3A using Dcaf8 KO mice (R00 phase). Overall, improving our understanding of DNMT3A protein function will shed light on how it regulates normal HSPC proliferation and hematopoiesis, and how its disruption contributes to CH. In this proposal, Dr. Yonezawa aims to fill this critical gap in knowledge and uncover the mechanisms of DNMT3A protein turnover to prevent its protein loss in CH using CRISPR screening, mass spectrometry, and a genetically engineered mouse model. Specifically, he will (1) Characterize USP11-dependent mechanisms controlling DNMT3A protein fate (K99), and (2) Determine the effects of DCAF8 on DNMT3A protein turnover in vivo (R00). This work will advance our understanding of normal hematopoiesis and CH and reveal mechanisms underlying DNMT3A protein regulation. If successful, this proposal could open new avenues to modulate and prevent CH. Dr. Yonezawa is a postdoctoral fellow at Baylor College of Medicine (BCM). His expertise includes computer science, protein engineering, molecular biology, and physiology with a focus on elucidating CH. His long-term goal is to elucidate the molecular mechanisms and protein-level regulation underlying hematopoiesis to modulate CH. The proposed research will provide new training for him in the fields of HSPCs and CH. The K99 phase work will be performed at BCM, a stellar research environment with cutting-edge facilities. Dr. Margaret (Peggy) Goodell — a leading expert on DNMT3A in normal and malignant hematopoiesis who has received numerous awards for her mentorship of promising young scientists — will serve as his mentor. Under her guidance and through his thoughtful career development plan, Dr. Yonezawa is well positioned to establish an independent research lab and become a leader himself in the field of normal and clonal hematopoiesis.


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: 2027 ( Subtotal = $0 )
2027	2026	BAYLOR COLLEGE OF MEDICINE	1 BAYLOR PLZ	HOUSTON	TX	77030	HARRIS	USA	Blood Diseases and Resources Research	000	1	10/27/2026	NEW	$0
														Subtotal = $0

Issue Date FY: 2026 ( Subtotal = $158,892 )
2026	2026	BAYLOR COLLEGE OF MEDICINE	1 BAYLOR PLZ	HOUSTON	TX	77030	HARRIS	USA	Blood Diseases and Resources Research	000	1	8/26/2026	NEW	$158,892
														Subtotal = $158,892

Grand Total All Awards = $158,892

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EXAMINING THE IMPACT OF DNMT3A PROTEIN REDUCTION ON NORMAL AND CLONAL HEMATOPOIESIS

Award Number: K99HL188297

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 09/01/2026

PERIOD OF PERFORMANCE END DATE: 07/31/2028

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