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EVI1 triggers metabolic reprogramming
strongly with OXPHOS activation to a greater extent than with leukemic stemness; and (iii) high OXPHOS activity in cells showing stemness properties induces tyrosine kinase inhibitor-resistance in those with chronic myelo- cytic leukemia.21,22,28 Here, we found that OXPHOS is acti- vated before glycolysis during onset of leukemia, thereby reconfirming the importance of mitochondrial metabo-
lism. A previous study reports that EVI1 plays an impor- tant role in metabolic regulation of leukemia, and that a metabolic pathway involving creatinine is the key.14 However, it is unclear how EVI1 controls metabolism and contributes to malignant alterations in MLL-r AML cells. The leukemia mouse model used in the present study did not show any alterations in creatine gene expression;
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HI
Figure 6. L-Asp inhibits growth of EVI1high acute myeloid leukemia (AML) tumor cells in vivo. (A) Schematic outline of the Evi1/MF9 mouse model treated with L-asp. Treatment began five days post transplantation. (B) L-asp led to a significant reduction in the number of circulating GFP+ AML cells in peripheral blood (n=8). (C) L-asp treatment extended the survival of recipient mice significantly (n=8). (D) The total number of whole AML cells in the bone marrow fell significantly after expo- sure to L-asp, but the percentage of L-GMP increased significantly. (E) The oxygen consumption rate (OCR) of L-asp-treated leukemia cells in MF9 mice was lower than that of vehicle-treated cells. (F) Schematic outline of the UCSD/AML1 xenograft mouse model treated with L-asp. Treatment began five days post transplanta- tion. (G-I) L-asp inhibited growth of AML tumors significantly (G). Tumor weight (H) and tumor size (I) (n=5).
P=0.0019
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