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The Role of HIF1A-DNMT3A axis in AML1/ETO-Driven Acute MyelogenousLeukemia

Award Number: R01CA248019
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/07/2020
PERIOD OF PERFORMANCE END DATE: 11/30/2025

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The Role of HIF1A-DNMT3A axis in AML1/ETO-Driven Acute MyelogenousLeukemia - The fusion protein AML 1/ETO (AE), resulting from the t(8;21) translocation, is a leukemia-initiating transcription factor that is frequently associated with acute myeloid leukemia (AML). Despite being defined as a favorable subtype of AML, many AE positive (AE+) patients relapse and die with largely unknown causes. It is also unclear how AE mediates a disease-predictable DNA methylation signature. The long-term goals are to elucidate further the mechanisms of AE+ AML leukemogenesis, discover new therapeutic targets and develop effective targeted therapies. The objective of this proposal is to explore the molecular basis of a disease-predictable DNA methylation signature underlying AE+ AML with a focus on the impact of hypoxia-independent HIF1alpha-DNMT3a signaling axis activation. The rationale underlying this proposal is that the hypoxia-independent HIF1alpha signaling activation is a new hallmark of cancer. In relation to this project, the hyperactive HIF1alpha signaling may be a disease-promoting factor and an epigenetic mediator in AE+ AML. HIF1alpha forms a feedforward loop with AE and transactivates DNMT3a, another prognostic marker in AE+ AML. HIF1alpha inhibition suppresses AML cell growth. However, the detailed mechanistic and biochemical links between HIF1alpha signaling and AE AML pathogenesis and disease recurrence are poorly defined. The central hypothesis is that HIF1alpha promotes AE leukemogenicity through enhancing AE transcriptional activities and modulating the AE-governed DNA methylation landscape in AML cells; therefore HIF1alpha may be a vulnerable and druggable target in AE+ AML. This hypothesis will be tested by pursuing three specific aims: 1.) Dissect the mechanistic details of how HIF1alpha is critical for AE-driven leukemogenesis; 2) Determine the role of HIF1alpha in AE-dependent DNA methylation; 3) Test pharmacological targeting of HIF1alpha as a therapeutic option for AE+ AML. To pursue our aims, we will use innovative combinations of biological techniques with unique transgenic and patient-derived xenograft (POX) mouse models, as well as innovative integration of aberrant HIF1alpha signaling and epigenetics in understanding and treating AE+ AML. The proposed research is significant, because it will disclose new genes/mechanistic pathways that are necessary for AE leukemogenicity, identify the therapeutic biomarkers, and discover new medicinal agents for AE+ AML. Further, it will thoroughly investigate the epigenetic and oncogenic role of HIF1alpha in cancer. The proximate expected outcomes are to demonstrate HIF1alpha-epigenetics crosstalk in defining AE-initiated transcriptional regulation and leukemia pathogenesis, and to establish the feasibility of using HIF1alpha inhibitors to enhance the therapeutic index of the existing treatment regimens. The results will have an important impact because they will advance our understanding of AE+ AML molecular pathology, aberrant epigenetics in leukemia and the oncogenic functions of hypoxia-independent HIF1alpha signaling in cancers. The findings will also lay the groundwork to develop newer strategies to better target AE+ AML.


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 = $635,657 )
2025	2025	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Cancer Biology Research	001	5	6/30/2025	NON-COMPETING CONTINUATION	$63,566
2025	2025	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Cancer Biology Research	000	5	11/19/2024	NON-COMPETING CONTINUATION	$572,091
														Subtotal = $635,657

Issue Date FY: 2024 ( Subtotal = $603,874 )
2024	2024	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Cancer Biology Research	000	4	11/30/2023	NON-COMPETING CONTINUATION	$572,092
2024	2024	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Cancer Biology Research	001	4	4/16/2024	NON-COMPETING CONTINUATION	$31,782
														Subtotal = $603,874

Issue Date FY: 2023 ( Subtotal = $668,694 )
2023	2023	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Cancer Biology Research	001	3	2/9/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$668,694
2023	2023	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Cancer Biology Research	003	3	6/14/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$618,378
2023	2022	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Cancer Biology Research	000	2	2/9/2023	NON-COMPETING CONTINUATION	$0
2023	2022	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Cancer Biology Research	002	2	6/14/2023	NON-COMPETING CONTINUATION	-$618,378
														Subtotal = $668,694

Issue Date FY: 2022 ( Subtotal = $646,651 )
2022	2022	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Cancer Biology Research	001	2	5/20/2022	NON-COMPETING CONTINUATION	$52,786
2022	2022	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Cancer Biology Research	000	2	1/28/2022	NON-COMPETING CONTINUATION	$593,865
														Subtotal = $646,651

Issue Date FY: 2021 ( Subtotal = $681,866 )
2021	2021	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Cancer Biology Research	000	1	12/7/2020	NEW	$681,866
														Subtotal = $681,866

Grand Total All Awards = $3,236,742

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The Role of HIF1A-DNMT3A axis in AML1/ETO-Driven Acute MyelogenousLeukemia

Award Number: R01CA248019

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 12/07/2020

PERIOD OF PERFORMANCE END DATE: 11/30/2025

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