Monday, June 30, 2025 6/30/2025

Role of the TET1 short isoform in MDS development and maintenance

Award Number: R01HL157539
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/20/2022
PERIOD OF PERFORMANCE END DATE: 12/31/2025

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Role of the TET1 short isoform in MDS development and maintenance - PROJECT SUMMARY Recent studies have revealed pervasive transcriptional regulation through alternative promoters in normal tissues and cancer. How the majority of alternative promoters contribute to tumor formation, diagnosis or treatment remains unknown. Tet1 was first identified as an MLL partner in AML. It belongs to the Tet (ten- eleven translocation) family of proteins (Tet1/2 and Tet3), which oxidize 5-methylcytosine (5mC) into 5- hydroxymethylcytosine (5hmC), and other oxi-mC intermediates, thereby facilitating DNA demethylation. Interestingly, we found that a short isoform of TET1 (referred to as TET1-S), which contains a catalytic domain but lacks the N-terminal CXXC domain, and is under control of an alternative promoter, was expressed in human bone marrow (BM) cells. Additionally, TET1-S was upregulated in BM cells from Myelodysplastic Syndrome (MDS) patients as compared to healthy individuals. We showed that TET1-S is expressed in BM cells at a much higher level compared with TET1-F. However, its role in the hematopoietic system is unknown. Based on our preliminary results, we hypothesize that Tet1-S plays an important role in the maintenance of hematopoietic stem cells (HSCs) and its upregulation contributes to the development of MDS by disrupting normal function of HSCs and hematopoiesis. To test this hypothesis, we will determine 1) the oncogenic role and underlying mechanisms of Tet1-S in the pathogenesis of MDS, 2) whether Tet1-S is required for the development of MDS, and 3) the molecular mechanisms by which Tet1-S regulates gene expression in HSPCs and erythroid progenitor cells. We will employ multiple genomic approaches to systematically analyze the progressive effects of Tet1-S overexpression on 5mhC/mC distribution, chromatin accessibility and gene expression in hematopoietic stem/progenitor cells. Our work will provide new insights into the distinct role of TET1-S upregulation in the pathogenesis of MDS as well as its specific role and mechanisms in maintaining epigenetic landscapes and gene regulation in HSPCs.


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: 2025 ( Subtotal = $481,940 )
2025	2025	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Blood Diseases and Resources Research	000	4	12/20/2024	NON-COMPETING CONTINUATION	$481,940
														Subtotal = $481,940

Issue Date FY: 2024 ( Subtotal = $524,779 )
2024	2024	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Blood Diseases and Resources Research	001	3	6/20/2024	NON-COMPETING CONTINUATION	$42,839
2024	2024	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Blood Diseases and Resources Research	000	3	1/9/2024	NON-COMPETING CONTINUATION	$481,940
														Subtotal = $524,779

Issue Date FY: 2023 ( Subtotal = $535,489 )
2023	2023	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Blood Diseases and Resources Research	000	2	1/25/2023	NON-COMPETING CONTINUATION	$535,489
														Subtotal = $535,489

Issue Date FY: 2022 ( Subtotal = $535,489 )
2022	2022	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Blood Diseases and Resources Research	000	1	1/19/2022	NEW	$535,489
														Subtotal = $535,489

Grand Total All Awards = $2,077,697

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Role of the TET1 short isoform in MDS development and maintenance

Award Number: R01HL157539

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/20/2022

PERIOD OF PERFORMANCE END DATE: 12/31/2025

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