Pallavi Rani, Gatti Elena, Durfort Tiphanie, Stendardo Massimo, Ravasio Roberto, Leonardi Tommaso, Falvo Paolo, Duso Bruno Achutti, Punzi Simona, Xieraili Aobuli, Polazzi Andrea, Verrelli Doriana, Trastulli Deborah, Ronzoni Simona, Frascolla Simone, Perticari Giulia, Elgendy Mohamed, Varasi Mario, Colombo Emanuela, Giorgio Marco, Lanfrancone Luisa, Minucci Saverio, Mazzarella Luca, Pelicci Pier Giuseppe
Department of Experimental Oncology, IEO European Institute of Oncology IRCCS, Milan, Italy.
Center for Genomic Science of IIT@SEMM, Fondazione Istituto Italiano di Tecnologia, Milan, Italy.
Nat Commun. 2024 Jan 27;15(1):828. doi: 10.1038/s41467-023-44348-y.
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.
热量限制（CR）已证实具有抗癌作用，但其临床相关性和分子机制在很大程度上仍不明确。在此，我们研究了CR对几种急性髓系白血病小鼠模型的影响，包括急性早幼粒细胞白血病，这是一种受肥胖严重影响的亚型。在最初显著的抗肿瘤作用之后，致命疾病总是会再次出现。起初，CR导致细胞周期受限、细胞凋亡以及对TOR和胰岛素/IGF1信号传导的抑制。相反，复发与白血病起始细胞的非基因选择以及双链RNA（dsRNA）传感和干扰素（IFN）信号基因的下调有关。CR诱导的适应性表型对LSD1的药理学或基因消融高度敏感，LSD1是一种调节干细胞和dsRNA/IFN信号传导的赖氨酸去甲基化酶。CR + LSD1抑制导致dsRNA/IFN信号重新激活、大量依赖RNASEL的细胞凋亡，并在约90%的小鼠中完全根除白血病。重要的是，通过将LSD1消融与胰岛素/IGF1的药理学抑制剂或双重PI3K/MEK阻断相结合，可以在体内和体外模拟CR-LSD1相互作用。从机制上讲，胰岛素/IGF1抑制通过抑制抗凋亡因子CFLAR使母细胞对LSD1诱导的死亡敏感。CR和LSD1抑制在患者来源的AML和三阴性乳腺癌异种移植中也具有协同作用。我们的数据为多种肿瘤的表观代谢药物联合应用提供了理论依据。
