Tuesday, August 19, 2025 8/19/2025

Mitochondrial NAD+ in Acute Myeloid Leukemias

Award Number: R01CA272490
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/24/2023
PERIOD OF PERFORMANCE END DATE: 07/31/2028

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Mitochondrial NAD+ in Acute Myeloid Leukemias - PROJECT SUMMARY Targeting mitochondrial metabolism is an active area of research in Acute Myeloid Leukemia (AML). The cumulative data indicate that AML cells have heightened mitochondrial activity and prefer glutamine as a carbon source compared to noncancerous cells. Nevertheless, a challenge that emerges when trying to target these vulnerabilities one at a time is the continued presence of treatment-refractory AML cells, which ultimately result in relapse or developed resistance. The likely causes are the adaptable nature of metabolic pathways and cell-to-cell variability, either due to local environment or genetics. We propose that loss of mitochondrial nicotinamide adenine dinucleotide (NAD+) will simultaneously block multiple metabolic pathways used by AML with minimal toxicity in healthy cells. We recently published that the SLC25A51 transporter is a critical regulator of mitochondrial NAD+ levels in human cells. SLC25A51 is directly responsible for NAD+ import, and modulation of SLC25A51 expression controls the concentrations of NAD+ in the mitochondrial matrix. Loss of SLC25A51 resulted in depleted NAD+ only in mitochondria and not throughout the whole cell. Until now, there has been no way to selectively deplete mitochondrial NAD+ through an endogenous target. Notably, we have found a broad vulnerability across AML cells to SLC25A51 depletion, including lines that previously were found to escape Complex I inhibition. This proposal will determine the extent that SLC25A51 impacts AML in vivo, elucidate the pathways that this transporter supports, and determine the molecular mechanisms controlling its expression. As there are limited treatment options for patients, the long-term benefit of this work is to establish a rationale for targeting mitochondrial NAD+ through SLC25A51 and to identify additional AML therapeutic approaches.


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 = $522,539 )
2025	2025	UNIVERSITY OF TEXAS AT AUSTIN	110 INNER CAMPUS DR	AUSTIN	TX	78712	TRAVIS	USA	Cancer Biology Research	000	3	8/1/2025	NON-COMPETING CONTINUATION	$522,539
														Subtotal = $522,539

Issue Date FY: 2024 ( Subtotal = $496,412 )
2024	2024	UNIVERSITY OF TEXAS AT AUSTIN	110 INNER CAMPUS DR	AUSTIN	TX	78712	TRAVIS	USA	Cancer Biology Research	000	2	7/19/2024	NON-COMPETING CONTINUATION	$496,412
														Subtotal = $496,412

Issue Date FY: 2023 ( Subtotal = $522,539 )
2023	2023	UNIVERSITY OF TEXAS AT AUSTIN	110 INNER CAMPUS DR	AUSTIN	TX	78712	TRAVIS	USA	Cancer Biology Research	000	1	8/24/2023	NEW	$522,539
														Subtotal = $522,539

Grand Total All Awards = $1,541,490

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Mitochondrial NAD+ in Acute Myeloid Leukemias

Award Number: R01CA272490

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/24/2023

PERIOD OF PERFORMANCE END DATE: 07/31/2028

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