Increased small extracellular vesicle secretion after chemotherapy via upregulation of cholesterol metabolism in acute myeloid leukaemia

Most patients with acute myeloid leukaemia (AML) experience disease recurrence after chemotherapy largely due to the development of drug resistance. Small extracellular vesicles (sEVs) are known to play a significant role in leukaemia drug resistance by delivery of anti-apoptotic proteins and genes conferring resistance to recipient cells. sEV levels are elevated in AML patients' plasma at the time of diagnosis and remain elevated in complete remission after chemotherapy. The mechanism of enhanced sEV secretion in AML is unknown. We speculated that cholesterol synthesis by AML blasts may be related to elevated sEV secretion. Intracellular levels of cholesterol and of HMGCR (3-hydroxy-3-methyl-glutaryl-coenzyme A reductase), the rate-limiting enzyme in cholesterol synthesizing mevalonate pathway, significantly increased in cultured AML cells or primary human non-malignant cells treated with cytarabine or decitabine. Concomitantly, levels of sEVs produced by these cells also increased. Treatment with an HMGCR inhibitor, Simvastatin, or siRNAs targeting HMGCR blocked the chemotherapy-induced enhancement of sEV secretion in AML cells. sEVs carry HMGCR and chemotherapy enhances HMGCR levels in sEVs. HMGCR(+)sEVs upregulate intracellular cholesterol and promote AML cell proliferation. A pharmacologic blockade of HMGCR emerges as a potential future therapeutic option for disrupting sEV signalling leading to cholesterol-driven chemo-resistance in AML.