Combination of caloric restriction and lysine-specific demethylase 1 (LSD1) inhibition in the treatment of acute myeloid leukemia
Session type: Proffered paper sessions
Metabolic modulation of tumor growth by caloric-restriction (CR) has emerged as a novel non-toxic adjuvant therapy and currently being tested in several tumors. However, its therapeutic potential in Acute Promyelocytic leukemia (APL), a subtype of Acute myeloid leukemia sensitive to body mass index, is not studied.
APL cells were generated in the transgenic mouse model of PML-RARA in the C57BL/6-Ly5.2. The leukemia developed in these mice can be transplanted serially and retain its similarities with human APLs in the transplanted mice. Mice transplanted with primary leukemias were subjected to 30% CR or Standard Diet (SD). The effect of CR alone or in combination with the Lysine-Specific Demethylase 1 (LSD1) inhibitor on mouse survival, Leukemia Initiating Cell (LIC) frequency, and on transcriptomic and metabolic parameters were determined. IGF1/Insulin inhibitor OSI-906 was used as a CR mimetic in recipient mice or in vitro in APL cell line to study the interaction between CR and LSD1 inhibitor.
We found that CR reduced the total leukemic burden and increased the survival in APL transplanted mice. However, APL cells eventually become adapted to the CR environment and showed increased frequency of LICs. This adaptation was accompanied by dramatic transcriptional reprogramming characterized by increased oxidative phosphorylation, TCA cycle and decrease in interferon associated pathways in APL cells. Interestingly, we found CR-induced adaptive changes to be sensitive to LSD1 inhibition, a histone modifier previously implicated in regulation of both LICs and interferon pathways. Strikingly, co-treatment of leukemic mice with CR and LSD1 inhibitor resulted in complete eradication of the disease. Importantly, CR-LSD1 interaction could be modeled by combining LSD1 and the IGF1/Insulin inhibitor OSI-906. Mechanistically, LSD1 inhibition seems to rescue CR induced decrease in dsRNA/OAS1 dependent apoptosis.
Combination of caloric restriction and LSD1 inhibition is a promising therapeutic strategy and deserves further investigation.