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Mechanisms of clonal competition in age related clonal hematopoiesis

Award Number: K01DK142040
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 08/01/2025
PERIOD OF PERFORMANCE END DATE: 05/31/2028

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Mechanisms of clonal competition in age related clonal hematopoiesis - Project Summary/Abstract With age, hematopoietic stem cells (HSCs) accrue mutations, some of which provide a competitive advantage and lead to the expansion of clones bearing the mutations, a phenomenon called clonal hematopoiesis (CH). CH is associated with inflammation, susceptibility to infections, high risk of cardiovascular disease, and development of myeloproliferative disorders and cancer. Together, these conditions represent the leading causes of death in older adults. Recent studies indicate that ~95% of healthy middle-aged adults bear CH-associated mutations. Although adults with these mutations are at much higher risk of hematologic disorders, progression from CH to disease states still only occurs in a small subset of these individuals. Many genes are associated with CH, but mutations in DMNT3a represent a majority of CH-associated mutations. We have shown that, within DNMT3a mutant HSCs, expansion is driven by a small set of “super-competitor” clones. Given that higher variant allele frequencies (VAF) of DNMT3a mutations indicate higher risk for hematologic disease, identifying factors which drive expansion in these clones is of high clinical relevance. We conducted a CRISPR- based ex vivo expansion screen of genes that are upregulated in DNMT3a mutant cells. Results of the screen highlighted the gene SLC3a2, whose knockout inhibits rapid expansion and induces synthetic lethality in DNMT3a mutant cells ex vivo and in transplantation settings. This proposal seeks to investigate the mechanisms of clonal competition in CH via a three-pronged approach. To validate SLC3a2’s effects in vivo, we will assay the expansion of DNMT3a mutant, SLC3a2 knockout HSCs and their gene expression profiles in unperturbed hematopoiesis. SLC3a2 is a component of the CD98 complex, which has dual roles in amino acid transport and integrin-mediated adhesion. To dissect the functional mechanism of SLC3a2’s effects in clonal competition, we will conduct pharmacological and genetic disruptions to components of the complex required solely for amino acid transport, and perform metabolic assays aimed at either phenocopying or rescuing the effect of SLC3a2 KO. Lastly, we will assess SLC3a2’s role in human clonal hematopoiesis using human cord blood CD34+ cells genetically altered to model DNMT3a-mediated clonal hematopoiesis. As a postdoctoral fellow, Dr. Quach will conduct his research in the laboratory of Dr. Fernando Camargo at Boston Children’s Hospital. Dr. Quach will build on his solid background in hematology and translational research, developing new skills in single-cell transcriptomics and stem cell biology to generate insights into the mechanisms of clonal hematopoiesis. His mentor, Dr. Camargo, is an expert in hematopoiesis and has developed innovative technologies for cellular barcoding and clonal analysis. Dr. Camargo’s mentorship and expertise, a strong scientific advisory committee, and a rigorous research and training plan provide all the necessary elements for success in the proposed project and Dr. Quach’s transition to independence.


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 = $153,360 )
2026	2026	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	6/11/2026	NON-COMPETING CONTINUATION	$153,360
														Subtotal = $153,360

Issue Date FY: 2025 ( Subtotal = $154,860 )
2025	2025	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	8/1/2025	NEW	$154,860
														Subtotal = $154,860

Grand Total All Awards = $308,220

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Mechanisms of clonal competition in age related clonal hematopoiesis

Award Number: K01DK142040

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 08/01/2025

PERIOD OF PERFORMANCE END DATE: 05/31/2028

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