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Haematologica 2020 Volume 105(8):2118-2129
Acute Myeloid Leukemia
EVI1 triggers metabolic reprogramming associated with leukemogenesis and increases sensitivity to L-asparaginase
Yusuke Saito,1 Daisuke Sawa,1 Mariko Kinoshita,1 Ai Yamada,1 Sachiyo Kamimura1, Akira Suekane,2 Honami Ogoh,2 Hidemasa Matsuo,3 Souichi Adachi,3 Takashi Taga,4 Daisuke Tomizawa,5 Motomi Osato,6,7 Tomoyoshi Soga,8 Kazuhiro Morishita2 and Hiroshi Moritake1
1Division of Pediatrics, Faculty of Medicine, University of Miyazaki, Miyazaki; 2Division of Tumor and Cellular Biochemistry, University of Miyazaki, Miyazaki; 3Department of Human Health Science, Kyoto University, Kyoto; 4Department of Pediatrics, Shiga University of Medical Science, Shiga; 5Division of Leukemia and Lymphoma, Children’s Cancer Center, National Center for Child Health and Development, Tokyo; 6Cancer Science Institute, National University of Singapore, Singapore; 7International Research Center for Medical Sciences, Kumamoto University, Kumamoto and 8Institute for Advanced Biosciences, Keio University, Yamagata, Japan
ABSTRACT
Metabolic reprogramming of leukemia cells is important for survival, proliferation, and drug resistance under conditions of metabolic stress in the bone marrow. Deregulation of cellular metabolism, leading to development of leukemia, occurs through abnormally high expression of transcription factors such as MYC and Ecotropic Virus Integration site 1 protein homolog (EVI1). Overexpression of EVI1 in adults and children with mixed lineage leukemia-rearrangement acute myeloid leukemia (MLL-r AML) has a very poor prognosis. To identify a metabolic inhibitor for EVI1-induced metabolic reprogramming in MLL-r AML, we used an XFp extracellular flux analyzer to examine metabolic changes during leukemia development in mouse models of AML expressing MLL-AF9 and Evi1 (Evi1/MF9). Oxidative phosphorylation (OXPHOS) in Evi1/MF9 AML cells accelerated prior to activation of glycolysis, with a higher dependency on glutamine as an energy source. Furthermore, EVI1 played a role in glycol- ysis as well as driving production of metabolites in the tricarboxylic acid cycle. L-asparaginase (L-asp) exacerbated growth inhibition induced by glu- tamine starvation and suppressed OXPHOS and proliferation of Evi1/MF9 both in vitro and in vivo; high sensitivity to L-asp was caused by low expres- sion of asparagine synthetase (ASNS) and L-asp-induced suppression of glu- tamine metabolism. In addition, samples from patients with EVI1+MF9 showed low ASNS expression, suggesting that it is a sensitive marker of L- asp treatment. Clarification of metabolic reprogramming in EVI1+ leukemia cells may aid development of treatments for EVI1+MF9 refractory leukemia.
Introduction
Acute myeloid leukemia (AML) is a cancer of myeloid lineage that results in genetically heterogeneous disease. Chromosomal translocations leading to fusion of the mixed lineage leukemia gene (MLL1) are common alterations associated with aggressive de novo and therapy-related acute leukemia in children and adults.1,2
The ecotropic viral integration site-1 (EVI1) gene encodes a zinc finger protein that functions as a transcriptional regulator of hematopoietic stem cell self-renewal and long-term multilineage repopulating activity.3,4 Overexpression of EVI1 is an independent, adverse prognostic factor because of its association with reduced remission duration of AML with MLL rearrangement (MLL-r AML), particularly in patients harboring MLL-AF9 (MF9).5-7 EVI1 may play an important role in mainte- nance of cell quiescence and stem cell-like phenotypes in leukemia cells, thereby contributing to chemoresistance.8,9 Previously, we identified potential therapeutic
Correspondence:
HIROSHI MORITAKE
hiroshi_moritake@med.miyazaki-u.ac.jp
Received: May 2, 2019. Accepted: October 24, 2019. Pre-published: October 24, 2019.
doi:10.3324/haematol.2019.225953
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