Caloric Restriction (CR) has established anti-cancer effects, but its clinical relevance and molecular mechanism remain largely undefined. Here, we investigate CR's impact on several mouse models of Acute Myeloid Leukemias, including Acute Promyelocytic Leukemia, a subtype strongly affected by obesity. After an initial marked anti-tumor effect, lethal disease invariably re-emerges. Initially, CR leads to cell-cycle restriction, apoptosis, and inhibition of TOR and insulin/IGF1 signaling. The relapse, instead, is associated with the non-genetic selection of Leukemia Initiating Cells and the downregulation of double-stranded RNA (dsRNA) sensing and Interferon (IFN) signaling genes. The CR-induced adaptive phenotype is highly sensitive to pharmacological or genetic ablation of LSD1, a lysine demethylase regulating both stem cells and dsRNA/ IFN signaling. CR + LSD1 inhibition leads to the re-activation of dsRNA/IFN signaling, massive RNASEL-dependent apoptosis, and complete leukemia eradication in ~90% of mice. Importantly, CR-LSD1 interaction can 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 sensitizes blasts to LSD1-induced death by inhibiting the anti-apoptotic factor CFLAR. CR and LSD1 inhibition also synergize in patient-derived AML and triple-negative breast cancer xenografts. Our data provide a rationale for epi-metabolic pharmacologic combinations across multiple tumors.

Cancer Cell Biology Institute of Molecular Genetics of the Czech Academy of Sciences Prague CZ 14220 Czech Republic

Center for Genomic Science of Fondazione Istituto Italiano di Tecnologia Milan Italy

Department of Biomedical Sciences University of Padova Padova Italy

Department of Experimental Oncology IEO European Institute of Oncology IRCCS Milan Italy

Department of Hemato Oncology Universita' Statale di Milano Milan Italy

IFOM ETS The AIRC Institute of Molecular Oncology Milan Italy

Institute for Clinical Chemistry and Laboratory Medicine University Hospital and Faculty of Medicine Technische Universität Dresden Dresden Germany

Medical Clinic 1 University Hospital Carl Gustav Carus Technische Universität Dresden Dresden Germany

Mildred Scheel Early Career Center National Center for Tumor Diseases Dresden University Hospital and Faculty of Medicine Technische Universität Dresden Dresden Germany

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