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Y. Saito et al.
however, it did show that an advantage in terms of mito- chondrial metabolism-dependent energy production could be obtained by activating glutamine metabolism. Furthermore, we suggest that high EVI1 expression main- tains OXPHOS activity, even in differentiated cells, and contributes to treatment resistance. Although we did not identify the genes controlled directly by EVI1, we believe that ASNS, IDH2, and SLC1A5 are candidates. IDH2 is mutated in 8-19% of AML cases; therefore, a mutant
IDH2 inhibitor is under development. Future studies should examine whether metabolic reprogramming or increased 2-HG production are induced upon high expres- sion of IDH2.29 In addition, we identified L-asp as a meta- bolic inhibitor for EVI1+ leukemia. L-asp exerts an anti- tumor effect by depleting both asparagine and gluta- mine.30,31 Sensitivity to L-asp correlates with ASNS expres- sion, but the clinical marker is unknown.32
Although some AML cases are highly sensitive to L-asp,
ABC
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H
Figure 7. Low expression of ASNS in MF9 leukemia cells increases their sensitivity to L-asp. (A and B) Expression of the glutamine transporter (Slc1a5) and ASNS by MF9 leukemia cells. Expression of ASNS by Evi1/MF9 cells was significantly lower than that by wild-type (WT) cells. Expression of Slc1a5 by Evi1/MF9 cells was significantly higher than that by WT cells. (C-H) Gene expression in samples from JPLSG AML-05. In the acute myeloid leukemia (AML) with MLL rearrangement (MLL- r AML) cohort (n=48), there was no significant difference in ASNS expression between those with EVI1– and those with EVI1+ AML (C). (D) MF9 AML showed signif- icantly lower expression of ASNS than non-MF9 MLL-r AML. Expression of ASNS by EVI1– MF9 cells was significantly lower than that of EVI1– MF9 (n=28) (E) but not that of the non-MF9 cohort (n=20) (F). (G and H) Expression of IDH2 (G) and SLC1A5 (H) in the MF9 cohort.
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haematologica | 2020; 105(8)