Effect of Si-711, a dual sirtuin 1 and 2 inhibitor, on gene expression in chronic myeloid leukemia K-562 cells

The transcriptomic signature of chronic myeloid leukemia (CML) patients is characterized by heightened proliferation and mitochondrial metabolic activity. Sirtuin (SIRT)1 and SIRT2 are recognized as key regulators of metabolism homeostasis and cell proliferation/survival, and our network analyses unveiled their significant role in driving CML pathogenesis. Accordingly, we demonstrated the therapeutic potential of dual SIRT1/2 inhibition across diverse models. In particular, we investigated the effect of a dual SIRT1/2 inhibitor, which exhibits selective efficacy against imatinib-sensitive and -resistant CML cells. To get a better understanding of Si-7111’s mechanism of action, we performed RNA-seq analysis on K-562 CML cells. The transcriptomic signature induced by Si-711 revealed that SIRT1/2 inhibition disrupted the regulation of crucial transcription factors, including MYC, associated with the reprogramming of hallmark pathways associated with CML cell proliferation. This reprogramming was characterized by metabolic alterations leading to energy depletion and subsequent induction of regulated necrosis.