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The function and underlying mechanism of TET1 in myelodysplastic syndromes

Award Number: R01DK124116
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/10/2020
PERIOD OF PERFORMANCE END DATE: 12/31/2023

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The function and underlying mechanism of TET1 in myelodysplastic syndromes - PROJECT SUMMARY (ABSTRACT): Title: The function and underlying mechanism of TET1 in myelodysplastic syndromes. Background: Myelodysplastic syndromes (MDS) is a heterogenous group of clonal hematopoietic stem cell disorders, characterized by peripheral blood (PB) cytopenias (e.g., anemia, leukopenia, and thrombocytopenia). Although chromosomal abnormalities, gene mutations and some histone/DNA epigenetic changes have been reported in MDS, the molecular mechanisms underlying the pathogenesis of MDS have not been well understood. TET1, the founding member of the TET methylcytosine dioxygenase family, was first identified as a fusion partner of the MLL gene in acute myeloid leukemia (AML). In contrast to the previous thought that all three TET genes (TET1/2/3) may function as tumor suppressor genes in cancers, our recent work showed that TET1 is overexpressed in certain subtypes of AMLs, and plays a critical oncogenic role in the development of such AMLs. However, the role of TET1 in MDS remains unknown. Recently, in analysis of a genome-wide gene expression profiling dataset of a large cohort of human primary MDS patients, we found that TET1 is also aberrantly overexpressed in all the major subtypes of MDS analyzed, which was confirmed by qPCR in our in-house MDS samples. Tet1 is also overexpressed in various murine MDS models. We then showed that knockdown of TET1 expression substantially promoted differentiation of MDS cells, and forced expression of wild-type TET1 (but not catalytic inactive TET1 mutant) caused the opposite phenomenon. TET1 depletion also significantly inhibited MDS progression and diminished cytopenias in vivo. Furthermore, we have identified a set of potential/candidate target genes of TET1 in MDS, and some of them have been implicated in the pathogenesis of MDS. Objective/Hypothesis: TET1 plays an essential role in MDS pathogenesis through epigenetically regulating expression of a set of essential target genes. Specific Aims: (1) To determine whether TET1 is required for the development and maintenance of MDS; (2) To determine whether forced expression of TET1 can promote MDS development and progression, and whether TET1 function is dependent on its catalytic activity; and (3) To decipher the molecular mechanism(s) underlying the pathological role of TET1 in MDS. Study Design: 1) We will conduct loss-of-function studies in genetic animal MDS models and patient-derived xeno-transplantation (PDX) MDS models to determine whether Tet1/TET1 expression/function is required for both development and maintenance of MDS (Aim 1). 2) We will conduct gain-of-function studies with the above MDS models to determine whether forced expression of Tet1/TET1 can promote MDS development and progression via a catalytic activity-dependent mechanism (Aim 2). 3) We will perform genome-wide ChIP-seq, 5hmC-seq, and RNA-seq to identify all direct targets of TET1 in MDS, followed by the validation/functional studies of a set of top targets of TET1 in vitro and in vivo, to elucidate the molecular mechanism underlying TET1’s role (Aim 3).


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: 2024 ( Subtotal = $0 )
2024	2023	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	5/7/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $548,659 )
2023	2023	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	1/18/2023	NON-COMPETING CONTINUATION	$548,659
														Subtotal = $548,659

Issue Date FY: 2022 ( Subtotal = $554,854 )
2022	2022	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	1/11/2022	NON-COMPETING CONTINUATION	$499,368
2022	2022	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	3/30/2022	NON-COMPETING CONTINUATION	$55,486
														Subtotal = $554,854

Issue Date FY: 2021 ( Subtotal = $559,500 )
2021	2021	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	11/18/2020	NON-COMPETING CONTINUATION	$503,550
2021	2021	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	2/3/2021	NON-COMPETING CONTINUATION	$55,950
														Subtotal = $559,500

Issue Date FY: 2020 ( Subtotal = $564,921 )
2020	2020	BECKMAN RESEARCH INSTITUTE OF THE CITY OF HOPE	1500 DUARTE RD	DUARTE	CA	91010	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	3/9/2020	NEW	$564,921
														Subtotal = $564,921

Grand Total All Awards = $2,227,934

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The function and underlying mechanism of TET1 in myelodysplastic syndromes

Award Number: R01DK124116

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 03/10/2020

PERIOD OF PERFORMANCE END DATE: 12/31/2023

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