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Dissecting the canonical and non-canonical functions of Tet2 in hematopoietic stem cells and hematologic disorders

Award Number: R01HL148852
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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ABSTRACT Myelodysplastic syndromes (MDS) comprise a group of clonal hematologic malignancies characterized by ineffective hematopoiesis coupled with morphologic dysplasia, and generally remains incurable by existing non- transplant therapy. The Ten-eleven translocation (TET) proteins constitute a family of enzymes that assure proper regulation of gene expression through DNA demethylation, and TET2 is one of the most frequently mutated genes in MDS. Tet2’s roles in hematopoiesis have largely been studied in knockout mice; Tet2 deletion causes progressive defects in hematopoiesis, including the aberrant self-renewal of hematopoietic stem cells (HSCs), and Tet2-deficient mice develop a chronic myelomonocytic leukemia-like disease. However, as these mice lack the entire protein, it is not known how the non-catalytic functions of Tet2 contribute to HSC function and MDS pathogenesis. In order to delineate the catalytic and non-catalytic functions of Tet2, we have established Tet2 catalytically inactive mice. Using this new genetic mouse model, we have obtained the compelling evidence that Tet2 catalytic mutant mice have less pronounced hematologic phenotypes than Tet2 knockout mice. These preliminary findings led us to hypothesize that, in addition to its enzymatic roles in DNA hydroxylation/demethylation, Tet2 is critical for the proper governance of HSCs and suppression of MDS in a catalytic-independent manner. In this study, we will conduct a comparative epigenomic, transcriptomic and hematologic analyses of Tet2 catalytic mutant and knockout mice to establish the non-catalytic requirements of Tet2 in HSC homeostasis and MDS suppression. We have three main goals: (1) to determine the contributions of non-catalytic Tet2 functions to HSC self-renewal and differentiation, (2) to define the suppressive roles of non- catalytic functions of Tet2 in loss-of-Tet2-driven MDS, and (3) to identify non-catalytic targets of Tet2 responsible for suppressing aberrant HSC homeostasis and MDS development. The proposed research will have a major impact on the MDS field by defining the contribution of the non-catalytic functions of TET2 to MDS etiology, and can lead to new therapeutic approaches for the treatment and management of MDS and other hematologic disorders.


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 = $801,205 )
2025	2025	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Blood Diseases and Resources Research	001	5	12/3/2024	COMPETING CONTINUATION	$801,207
2025	2022	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Blood Diseases and Resources Research	000	4	11/25/2024	NON-COMPETING CONTINUATION	-$2
														Subtotal = $801,205

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2022	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Blood Diseases and Resources Research	000	4	3/6/2023	NON-COMPETING CONTINUATION	$0
2023	2022	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Blood Diseases and Resources Research	001	4	4/19/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $694,860 )
2022	2022	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Blood Diseases and Resources Research	000	4	6/8/2022	NON-COMPETING CONTINUATION	$694,860
														Subtotal = $694,860

Issue Date FY: 2021 ( Subtotal = $694,860 )
2021	2021	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Blood Diseases and Resources Research	000	3	6/11/2021	NON-COMPETING CONTINUATION	$694,860
														Subtotal = $694,860

Issue Date FY: 2020 ( Subtotal = $694,860 )
2020	2020	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Blood Diseases and Resources Research	000	2	6/11/2020	NON-COMPETING CONTINUATION	$694,860
														Subtotal = $694,860

Issue Date FY: 2019 ( Subtotal = $694,860 )
2019	2019	ALBERT EINSTEIN COLLEGE OF MEDICINE, INC.	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Blood Diseases and Resources Research	001	1	6/27/2019	NEW	$0
2019	2019	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Blood Diseases and Resources Research	003	1	7/24/2019	NEW	$694,860
2019	2019	ALBERT EINSTEIN COLLEGE OF MEDICINE, INC.	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Blood Diseases and Resources Research	000	1	6/24/2019	NEW	$694,860
2019	2019	ALBERT EINSTEIN COLLEGE OF MEDICINE, INC.	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Blood Diseases and Resources Research	002	1	7/17/2019	NEW	-$694,860
														Subtotal = $694,860

Grand Total All Awards = $3,580,645

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Dissecting the canonical and non-canonical functions of Tet2 in hematopoietic stem cells and hematologic disorders

Award Number: R01HL148852

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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