Combination of caloric restriction and lysine-specific demethylase 1 (LSD1) inhibition in the treatment of acute myeloid leukemia


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Rani Pallavi1,Luca Mazzarella1,Tiphanie Durfort1,Elena Gatti1,Bruno Achutti Duso1,Massimo Stendardo1,Luciano Giaco1,Ciro Mercurio2,Mario Varasi2,Marco Giorgio1,Saverio Minucci1,Pier Giuseppe Pelicci1
1European Institute of Oncology,2FIRC Institute of Molecular Biology

Abstract

Background

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.

Method

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.

Results

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.

Conclusion

Combination of caloric restriction and LSD1 inhibition is a promising therapeutic strategy and deserves further investigation.