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 antiapoptotic 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.

Therapies for Acute Myelogenous Leukemia (AML) have not been successful largely due to disease recurrence after chemotherapy. Recent studies showed that exosomes play a significant role in leukemia chemo-resistance. Levels of exosomes in patients’ plasma are elevated at AML diagnosis relative to those in normal donors’ plasma and remain elevated when patients reach complete remission (CR). These exosomes carry immunosuppressive molecules, interfere with anti-leukemia immunity and promote blast chemoresistance. We hypothesized that the development of methods for blocking exosome secretion could benefit AML patients. To understand the mechanisms of enhanced exosome secretion in AML blasts, we focused on cholesterol synthesis in blasts and its relationship to exosome secretion. Cholesterol metabolism in AML cell lines after treatment of chemotherapeutic agents (cytarabine and decitabine) was shown to enhance (p<0.005) intracellular level of cholesterol and the expression of HMGCR (3-hydroxy-3-methyl-glutaryl-coenzyme A reductase), the rate-limiting enzyme in cholesterol synthesizing mevalonate pathway. Consequently, the production of exosomes in the cell culture supernatants increased (p<0.02). Treatment with an HMGCR inhibitor, simvastatin, or siRNAs targeting HMGCR blocked (p<0.02) the chemotherapy- induced enhancement of exosome production. Exosomes carry HMGCR and chemotherapy enhanced HMGCR levels on exosomes. Our results show that chemotherapy enhances exosome secretion by increasing cholesterol synthesis in leukemic blasts. A pharmacologic blockade of HMGCR with simvastatin emerges as a potential future therapeutic for exosomes in AML. Note: This abstract was not presented at the meeting. Citation Format: Chang-Sook Hong, Emily J. Jeong, Beatrice Razzo, Michael Boyiadzis, Theresa L. Whiteside. Chemotherapy enhances exosome secretion via upregulation of cholesterol metabolism in acute myeloid leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 993.

No abstract