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Targeting Cellular Metabolism in Acute Myeloid Leukemia and the Role of Patient Heterogeneity

Authors :
Ida Sofie Grønningsæter
Håkon Reikvam
Elise Aasebø
Sushma Bartaula-Brevik
Tor Henrik Tvedt
Øystein Bruserud
Kimberley Joanne Hatfield
Source :
Cells, Vol 9, Iss 5, p 1155 (2020)
Publication Year :
2020
Publisher :
MDPI AG, 2020.

Abstract

Acute myeloid leukemia (AML) is an aggressive blood cancer resulting in accumulation of immature, dysfunctional blood cells in the bone marrow. Changes in cell metabolism are features of many cancers, including AML and this may be exploited as a therapeutic target. In this study we investigated the in vitro antileukemic effects of seven metabolic inhibitors that target different metabolic pathways. The metabolic inhibitors were tested on AML cells derived from 81 patients using proliferation and viability assays; we also compared global gene expression and proteomic profiles for various patient subsets. Metformin, 2DG, 6AN, BPTES and ST1326 had strong antiproliferative and proapoptotic effects for most patients, whereas lonidamine and AZD3965 had an effect only for a minority. Antiproliferative effects on AML cells were additive when combined with the chemotherapeutic agent AraC. Using unsupervised hierarchical clustering, we identified a strong antiproliferative effect on AML cells after treatment with metabolic inhibitors for a subset of 29 patients. Gene expression and proteomic studies suggested that this subset was characterized by altered metabolic and transcriptional regulation. In addition, the Bcl-2 inhibitor venetoclax, in combination with 2DG or 6AN, increased the antiproliferative effects of these metabolic inhibitors on AML cells. Therapeutic targeting of cellular metabolism may have potential in AML, but the optimal strategy will likely differ between patients.

Details

Language :
English
ISSN :
20734409
Volume :
9
Issue :
5
Database :
Directory of Open Access Journals
Journal :
Cells
Publication Type :
Academic Journal
Accession number :
edsdoj.5f40a3c0e3e740798134cb98273fe632
Document Type :
article
Full Text :
https://doi.org/10.3390/cells9051155