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The role of YTHDC1 in normal and malignant hematopoiesis

Award Number: R01CA259576
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/10/2022
PERIOD OF PERFORMANCE END DATE: 07/28/2025

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The role of YTHDC1 in normal and malignant hematopoiesis - ABSTRACT N6-methylation (m6A) is one of the most abundant endogenous modifications in eukaryotic mRNA. Accumulating evidence suggests that dynamic m6A RNA methylation has significant roles in multiple biological processes, and tumorigenesis by introducing another layer of post-transcriptional regulation of gene expression. Acute myeloid leukemia (AML), one of the most common types of acute leukemia, is a hematological malignant disease. In AML patients, gene mutations and genomic rearrangements often occur in hematopoietic stem/progenitor cells (HSPCs), and turn HSPCs into leukemia stem cells (LSCs), which play a central role in the development and maintenance of AML. To date, there is not an effective targeted therapy available for AML. The roles of m6A modification and its associated machinery in the pathogenesis of AML and the maintenance of LSCs/LICs remain elusive. As a nuclear m6A RNA reader that has been identified, YTHDC1 recognizes nuclear m6A-sites and acts as a critical mediator of nuclear m6A. YTHDC1 has unique roles in the regulation of nuclear RNA splicing, alternative polyadenylation, nuclear export and decay. However, its role and function in AML has not been reported yet. Our preliminary studies showed that YTHDC1 is overexpressed in human AML. We found that YTHDC1 is required for MLL-AF9-induced leukemogenesis and the survival of LSC/LIC. Thus, we hypothesize that YTHDC1 upregulation leads to post-transcriptional deregulation of a set of genes that are required for the maintenance of LSCs, thereby contributing to the pathogenesis of AML. In this proposal, we will determine 1) the role of YTHDC1 as a nuclear RNA reader in the initiation, development and maintenance of AML by regulating LSC self-renewal and survival; and 2) the underlying molecular mechanisms that mediate the role of YTHDC1 in the pathogenesis of AML. We will employ both genetic murine models as well as patient-derived xeno-transplantation (PDX) models to investigate the role of YTHDC1 in the pathogenesis of AML in vivo, and will combine transcriptome and epitranscriptome analysis to identify the key downstream targets and associated downstream pathways that mediate the role of YTHDC1 in leukemogenesis. In addition, we will elucidate molecular mechanisms by which YTHDC1 epigenetically controls the expression of its direct targets in AML cells. Our studies will define the unrecognized role of YTHDC1 in the AML development/maintenance and regulation of LSC/LIC self-renewal, quiescence and survival, and clarify the underlying mechanisms of YTHDC1. Thus, success of our project will provide new insights into the complicated mechanisms underlying epitranscriptomic regulation of leukemogenesis.


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 = $0 )
2026	2025	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Cancer Biology Research	001	5	2/10/2026	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$386,344
2026	2025	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Cancer Biology Research	002	4	2/19/2026	NON-COMPETING CONTINUATION	$0
2026	2025	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Cancer Biology Research	000	4	2/10/2026	NON-COMPETING CONTINUATION	-$386,344
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $450,534 )
2025	2025	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Cancer Biology Research	000	4	4/7/2025	NON-COMPETING CONTINUATION	$405,481
2025	2025	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Cancer Biology Research	001	4	5/22/2025	NON-COMPETING CONTINUATION	$45,053
														Subtotal = $450,534

Issue Date FY: 2024 ( Subtotal = $428,007 )
2024	2024	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Cancer Biology Research	000	3	4/18/2024	NON-COMPETING CONTINUATION	$428,007
														Subtotal = $428,007

Issue Date FY: 2023 ( Subtotal = $441,524 )
2023	2023	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Cancer Biology Research	000	2	4/28/2023	NON-COMPETING CONTINUATION	$441,524
														Subtotal = $441,524

Issue Date FY: 2022 ( Subtotal = $463,659 )
2022	2022	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Cancer Biology Research	000	1	5/10/2022	NEW	$463,659
														Subtotal = $463,659

Grand Total All Awards = $1,783,724

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The role of YTHDC1 in normal and malignant hematopoiesis

Award Number: R01CA259576

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/10/2022

PERIOD OF PERFORMANCE END DATE: 07/28/2025

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