journal contribution
posted on 2024-04-01, 07:23 authored by Andrew J. Monteith, Haley E. Ramsey, Alexander J. Silver, Donovan Brown, Dalton Greenwood, Brianna N. Smith, Ashley D. Wise, Juan Liu, Sarah D. Olmstead, Jackson Watke, Maria P. Arrate, Agnieszka E. Gorska, Londa Fuller, Jason W. Locasale, Matthew C. Stubbs, Jeffrey C. Rathmell, Michael R. Savona Figure S1: Glutaminolysis and fatty acid oxidation does not allow MOLM-13 to metabolically bypass BET inhibition. (A) MV-4-11 and MOLM-13 cells were cultured for 72 hr with BETi (0.15 µM) and viability quantified using a fluorescent plate reader. Viability was quantified relative to cells treated with vehicle control. Each point represents the mean (technical triplicate) value obtained from cells from an individual experiment (n=3). (B-E) MV-4-11 and MOLM-13 cells were loaded with a CellTrace dye and cultured for 72 hr with BETi and either (B-C) V-0302 (25 µM) or (D-E) etomoxir (150 µM). (B, D) To assess replication, CellTrace fluorescence intensity was quantified by flow cytometry and (C, E) viability was quantified in a fluorescent plate reader. Replication and viability were quantified relative to cells treated with vehicle control. (F) Raw CT values from qPCR experiment in Fig. 2A. Each point represents (B, D) the median fluorescent intensity (MFI) from or (C, E) the mean (technical triplicate) value obtained from cells from an individual experiment (n=3). (A) Paired t test or (B-E) Two-way ANOVA with Sidak’s multiple comparisons test (**P ≤ 0.01, ns = not significant).
Funding
National Cancer Institute (NCI)
United States Department of Health and Human Services
Find out more...Division of Diabetes, Endocrinology, and Metabolic Diseases (DEM)
Leukemia and Lymphoma Society (LLS)
History
ARTICLE ABSTRACT
Impairing the BET family coactivator BRD4 with small-molecule inhibitors (BETi) showed encouraging preclinical activity in treating acute myeloid leukemia (AML). However, dose-limiting toxicities and limited clinical activity dampened the enthusiasm for BETi as a single agent. BETi resistance in AML myeloblasts was found to correlate with maintaining mitochondrial respiration, suggesting that identifying the metabolic pathway sustaining mitochondrial integrity could help develop approaches to improve BETi efficacy. Herein, we demonstrated that mitochondria-associated lactate dehydrogenase allows AML myeloblasts to utilize lactate as a metabolic bypass to fuel mitochondrial respiration and maintain cellular viability. Pharmacologically and genetically impairing lactate utilization rendered resistant myeloblasts susceptible to BET inhibition. Low-dose combinations of BETi and oxamate, a lactate dehydrogenase inhibitor, reduced in vivo expansion of BETi-resistant AML in cell line and patient-derived murine models. These results elucidate how AML myeloblasts metabolically adapt to BETi by consuming lactate and demonstrate that combining BETi with inhibitors of lactate utilization may be useful in AML treatment.
Lactate utilization allows AML myeloblasts to maintain metabolic integrity and circumvent antileukemic therapy, which supports testing of lactate utilization inhibitors in clinical settings to overcome BET inhibitor resistance in AML.See related commentary by Boët and Sarry, p. 950
