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The Role of DLST in Leukemogenesis

Award Number: R01CA215059
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/07/2018
PERIOD OF PERFORMANCE END DATE: 07/31/2025

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The Role of DLST in Leukemogenesis - PROJECT SUMMARY Despite treatment improvements, leukemia-associated mortality is still high owing to drug resistance and disease relapse. Metabolic reprogramming is a hallmark of cancer, and represents an exciting new area of targeted therapy. Therefore, identification of the key enzyme responsible for metabolic reprogramming and elucidation of its mechanisms of action in treatment-resistant leukemic cells could lead to novel therapeutic strategies against the unique metabolic dependence of these cancer cells. We recently reported that dihydrolipoamide S-succinyltransferase (DLST) serves as a critical metabolic “oncorequisite” enzyme in MYC- driven leukemogenesis. MYC-dependent T-acute lymphoblastic leukemia (T-ALL) cells reprogram metabolism by stabilizing DLST protein, and rely heavily on its elevated levels for proliferation and survival. Heterozygous loss of dlst in zebrafish does not impair development yet significantly delays the onset of MYC-induced T-ALL that resembles a major subtype of human disease with poor prognosis. DLST is a transferase in the tricarboxylic acid (TCA) cycle and mediates the conversion of α-ketoglutarate (α-KG) to succinyl-CoA. α-KG is a key cycle intermediate that simultaneously functions as an obligatory cofactor for α-KG-dependent dioxygenases (α-KGDO, e.g., demethylases), thus linking cellular metabolism with epigenetic controls of the cell. We hypothesize that: DLST protein stabilization accelerates α-KG conversion, enhances TCA cycle function, and suppresses α-KGDO activities, thus promoting leukemic cell proliferation and survival. In Aim 1 of this application we will apply genetic, pharmacological and biochemical approaches to determine the mechanisms by which DLST is stabilized in MYC-overexpressing T-ALL cells and identify novel DLST interactors including its E3 ligase(s). The zebrafish T-ALL model will then be utilized to define the role of key DLST regulators/interactors in T-ALL pathogenesis. In Aim 2, we will combine the analyses of the in vivo zebrafish model and human T-ALL cells to identify the biochemical and epigenetic changes associated with DLST inactivation, as well as functionally characterize key α-KGDO regulated by DLST in T-ALL pathogenesis. In Aim 3, we will investigate the targetability and compensatory pathways of DLST in relapsed/refractory T-ALL by using our newly identified DLST inhibitor and in vivo animal models including murine patient-derived xenografts. The innovation of this application lies in the study of DLST as a novel “oncorequisite” enzyme that regulates both metabolism and epigenetic status of the cell in a physiologically relevant in vivo zebrafish system. Indeed, this innovative system has enabled us to identify MYC and AMP-activated protein kinase as regulators for DLST and isocitrate dehydrogenase 2 as its compensatory gene. This research is significant in that it will deepen our understanding of leukemia pathogenesis and cancer metabolism, as well as the metabolo-epigenetic connections in MYC-dependent leukemic cells, with the long-term goal of developing novel therapeutic strategies against DLST-mediated pathways in cancer cells.


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 = -$527 )
2026	2022	TRUSTEES OF BOSTON UNIVERSITY	85 EAST NEWTON ST # M-921	BOSTON	MA	02118	SUFFOLK	USA	Cancer Cause and Prevention Research	000	5	12/8/2025	NON-COMPETING CONTINUATION	-$527
														Subtotal = -$527

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2022	TRUSTEES OF BOSTON UNIVERSITY	85 EAST NEWTON ST # M-921	BOSTON	MA	02118	SUFFOLK	USA	Cancer Cause and Prevention Research	000	5	7/12/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $441,720 )
2022	2022	TRUSTEES OF BOSTON UNIVERSITY	85 E NEWTON ST M-921	BOSTON	MA	02118	SUFFOLK	USA	Cancer Biology Research	002	5	8/1/2022	SUPPLEMENT FOR EXPANSION	$71,831
2022	2022	TRUSTEES OF BOSTON UNIVERSITY	85 E NEWTON ST M-921	BOSTON	MA	02118	SUFFOLK	USA	Cancer Cause and Prevention Research	001	5	7/29/2022	NON-COMPETING CONTINUATION	$369,889
2022	2021	TRUSTEES OF BOSTON UNIVERSITY	85 E NEWTON ST M-921	BOSTON	MA	02118	SUFFOLK	USA	Cancer Cause and Prevention Research	000	4	10/18/2021	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $441,720

Issue Date FY: 2021 ( Subtotal = $429,919 )
2021	2021	TRUSTEES OF BOSTON UNIVERSITY	85 E NEWTON ST M-921	BOSTON	MA	02118	SUFFOLK	USA	Cancer Cause and Prevention Research	001	4	9/15/2021	SUPPLEMENT FOR EXPANSION	$73,298
2021	2021	TRUSTEES OF BOSTON UNIVERSITY	85 E NEWTON ST M-921	BOSTON	MA	02118	SUFFOLK	USA	Cancer Cause and Prevention Research	000	4	8/20/2021	NON-COMPETING CONTINUATION	$356,621
														Subtotal = $429,919

Issue Date FY: 2020 ( Subtotal = $392,723 )
2020	2020	TRUSTEES OF BOSTON UNIVERSITY	85 E NEWTON ST M-921	BOSTON	MA	02118	SUFFOLK	USA	Cancer Cause and Prevention Research	000	3	7/29/2020	NON-COMPETING CONTINUATION	$392,723
														Subtotal = $392,723

Issue Date FY: 2019 ( Subtotal = $366,641 )
2019	2019	TRUSTEES OF BOSTON UNIVERSITY	85 E NEWTON ST M-921	BOSTON	MA	02118	SUFFOLK	USA	Cancer Cause and Prevention Research	001	2	7/23/2019	NON-COMPETING CONTINUATION	$366,114
2019	2018	TRUSTEES OF BOSTON UNIVERSITY	85 E NEWTON ST M-921	BOSTON	MA	02118	SUFFOLK	USA	Cancer Cause and Prevention Research	000	1	12/21/2018	NEW	$527
														Subtotal = $366,641

Issue Date FY: 2018 ( Subtotal = $377,437 )
2018	2018	TRUSTEES OF BOSTON UNIVERSITY	85 E NEWTON ST M-921	BOSTON	MA	02118	SUFFOLK	USA	Cancer Cause and Prevention Research	000	1	8/7/2018	NEW	$377,437
														Subtotal = $377,437

Grand Total All Awards = $2,007,913

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The Role of DLST in Leukemogenesis

Award Number: R01CA215059

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/07/2018

PERIOD OF PERFORMANCE END DATE: 07/31/2025

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