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METABOLIC REGULATION IN LEUKEMIA-INITIATING CELLS

Award Number: R01CA193235
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2015
PERIOD OF PERFORMANCE END DATE: 06/30/2025

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METABOLIC REGULATION IN LEUKEMIA-INITIATING CELLS - AML is the most common acute leukemia in adults, and it appears increasingly with age. Despite overall improvement in the treatment of leukemia, AML still carries a devastating prognosis for elderly patients (less than 10% of patients survive for 5 years). Thus, new therapies for AML are necessary. AMPK is a metabolic regulator that promotes catabolism and inhibits anabolism, thereby maintaining metabolic homeostasis upon metabolic stress. Using mouse models and AMPK inhibitors, we demonstrated that AMPK inhibition renders AML sensitive to metabolic stress induced by dietary restriction (Saito et al. Cell Stem Cell. 2015). During this study, we noticed that AMPK deletion reduces acetyl-coA and histone acetylation in AML (Fig. 2), concomitant with decreased expression of critical leukemia-promoting genes such as Myc. Importantly, chromatin immunoprecipitation and sequencing (ChIP-seq) revealed that AMPK deletion reduces the occupancy of acetylated histones, all of which marks active genes and recruits transcriptional regulators. We thus hypothesized that AMPK links metabolism to epigenetics in AML by maintaining histone acetylation. In aim 1 we will determine whether the occupancy of transcriptional regulators in AML is regulated by AMPK. In aim 2, we will determine how metabolites and the metabolic enzymes that produces acetyl-coA regulate histone acetylation. In aim 3, we will determine how AMPK-mediated histone acetylation regulates human AML, by generating patient-derived xenograft models of AML. Taken together, this proposal will establish the link between metabolism and epigenetics, more specifically the links between acetyl-CoA metabolism, AMPK, and histone acetylation. We hypothesize that these interactions are essential to recruit transcriptional regulators to key leukemogenic genes. In the next funding cycle, we anticipate to unveil new insights that will inform us on how metabolic regulators could be targeted to sensitize AML to epigenetic drugs, paving the way to novel combinatorial therapies.


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	2024	BAYLOR COLLEGE OF MEDICINE	1 BAYLOR PLZ	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	10	11/20/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $438,806 )
2024	2024	BAYLOR COLLEGE OF MEDICINE	1 BAYLOR PLZ	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	10	6/27/2024	NON-COMPETING CONTINUATION	$438,806
														Subtotal = $438,806

Issue Date FY: 2023 ( Subtotal = $452,662 )
2023	2023	BAYLOR COLLEGE OF MEDICINE	1 BAYLOR PLZ	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	9	6/28/2023	NON-COMPETING CONTINUATION	$452,662
														Subtotal = $452,662

Issue Date FY: 2022 ( Subtotal = $452,662 )
2022	2022	BAYLOR COLLEGE OF MEDICINE	1 BAYLOR PLZ	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	8	6/24/2022	NON-COMPETING CONTINUATION	$452,662
														Subtotal = $452,662

Issue Date FY: 2021 ( Subtotal = $461,901 )
2021	2021	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	002	7	6/21/2021	NON-COMPETING CONTINUATION	$461,901
2021	2020	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	001	6	12/10/2020	COMPETING CONTINUATION	$4,465
2021	2019	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	5	12/10/2020	NON-COMPETING CONTINUATION	-$4,465
														Subtotal = $461,901

Issue Date FY: 2020 ( Subtotal = $498,469 )
2020	2020	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	001	6	7/4/2020	COMPETING CONTINUATION	$461,901
2020	2020	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	002	6	9/15/2020	COMPETING CONTINUATION	$36,568
2020	2019	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	5	6/25/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $498,469

Issue Date FY: 2019 ( Subtotal = $448,325 )
2019	2019	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	5	3/7/2019	NON-COMPETING CONTINUATION	$448,325
														Subtotal = $448,325

Issue Date FY: 2018 ( Subtotal = $462,191 )
2018	2018	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	001	4	5/23/2018	NON-COMPETING CONTINUATION	$46,220
2018	2018	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	4	3/13/2018	NON-COMPETING CONTINUATION	$415,971
														Subtotal = $462,191

Issue Date FY: 2017 ( Subtotal = $462,191 )
2017	2017	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	001	3	6/7/2017	NON-COMPETING CONTINUATION	$46,220
2017	2017	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	3	3/9/2017	NON-COMPETING CONTINUATION	$415,971
														Subtotal = $462,191

Issue Date FY: 2016 ( Subtotal = $462,191 )
2016	2016	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	2	3/17/2016	NON-COMPETING CONTINUATION	$462,191
														Subtotal = $462,191

Issue Date FY: 2015 ( Subtotal = $461,462 )
2015	2015	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	1	2/19/2015	NEW	$461,462
														Subtotal = $461,462

Grand Total All Awards = $4,600,860

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METABOLIC REGULATION IN LEUKEMIA-INITIATING CELLS

Award Number: R01CA193235

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/01/2015

PERIOD OF PERFORMANCE END DATE: 06/30/2025

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