LSD1 and caloric restriction in leukemia

Caloric Restriction (CR) or other dietary-restriction interventions are under intense scrutiny for their anti-tumor effects1–3. Their clinical relevance and underlying molecular mechanisms remain, however largely undefined. We investigated the effects of CR on several mouse cancer models, including Acute Promyelocytic Leukemia, a subtype of myeloid leukemias strongly affected by obesity4,5. Surprisingly, after an initial and marked anti-tumor effect, we invariably observed the re-emergence of even more aggressive disease. The transient anti-tumor effect was associated with cell-cycle restriction, apoptosis of leukemia cells, and inhibition of well-characterized CR-targeted pathways (TOR and insulin/IGF1 signaling). The relapse, instead, was associated with the non-genetic selection of Leukemia Initiating Cells (LICs) and the marked downregulation of genes involved in double-stranded RNA (dsRNA) sensing and Interferon signaling, known to induce RNASEL-dependent apoptosis and stem cell exhaustion. The CR-induced adaptive phenotype was highly-sensitive to pharmacological or genetic ablation of LSD1, a histone modifier regulating both stem cells and dsRNA/interferon signaling. CR+LSD1 inhibition led to re-activation of dsRNA/IFN signaling, massive RNASEL-dependent apoptosis, and, strikingly, complete leukemia eradication in ~90% of mice. Importantly, CR-LSD1 interaction could be modeled in vivo and in vitro by combining LSD1 ablation with pharmacological inhibitors of insulin/IGF1 or dual PI3K/MEK blockade. Mechanistically, insulin/IGF1 inhibition sensitized cells to LSD1-induced death by inhibiting the anti-apoptotic factor CFLAR. Finally, a synergy between CR and LSD1 inhibition was also observed in patient-derived xenografts of triple-negative breast cancer, suggesting epi-metabolic pharmacologic combinations as promising therapeutic strategies across the cancer spectrum.