Classic and targeted anti‐leukaemic agents interfere with the cholesterol biogenesis metagene in acute myeloid leukaemia: Therapeutic implications

Abstract

Despite significant advances in deciphering the molecular landscape of acute myeloid leukaemia (AML), therapeutic outcomes of this haematological malignancy have only modestly improved over the past decades. Drug resistance and disease recurrence almost invariably occur, highlighting the need for a deeper understanding of these processes. While low O 2 compartments, such as bone marrow (BM) niches, are well‐recognized hosts of drug‐resistant leukaemic cells, standard in vitro studies are routinely performed under supra‐physiologic (21% O 2 , ambient air) conditions, which limits clinical translatability. We hereby identify molecular pathways enriched in AML cells that survive acute challenges with classic or targeted therapeutic agents. Experiments took into account variations in O 2 tension encountered by leukaemic cells in clinical settings. Integrated RNA and protein profiles revealed that lipid biosynthesis, and particularly the cholesterol biogenesis branch, is a particularly therapy‐induced vulnerability in AML cells under low O 2 states. We also demonstrate that the impact of the cytotoxic agent cytarabine is selectively enhanced by a high‐potency statin. The cholesterol biosynthesis programme is amenable to additional translational opportunities within the expanding AML therapeutic landscape. Our findings support the further investigation of higher‐potency statin (eg rosuvastatin)–based combination therapies to enhance targeting residual AML cells that reside in low O 2 environments.

A Novel Prognostic Model for Acute Myeloid Leukemia Based on Gene Set Variation Analysis

“…Previous studies have shown that the cholesterol synthesis of AML cells increased significantly after being exposed to chemotherapy [ 13 ]. Inhibiting cholesterol synthesis can kill AML cells and sensitize them to chemotherapeutic drugs [ 14 , 15 ], suggesting that AML cells require higher levels of cholesterol to maintain survival compared with normal cells and that the imbalance of cholesterol homeostasis may lead to treatment failure. A phase 2 study of pravastatin in combination with idarubicin and cytarabine reported an encouraging response rate for relapsed AML [ 16 ] and improved overall survival for patients in the low-risk group [ 17 ].…”

Pharmacological inhibition of Carbonic Anhydrase IX and XII to enhance targeting of acute myeloid leukaemia cells under hypoxic conditions

“…Blasts were separated as described elsewhere. 38 The clinical characteristics of the patients from whom samples and tissues were derived are listed in Tables 1A and 1B .…”

“…Blasts were separated as described elsewhere. 38 The clinical characteristics of the patients from whom samples and tissues were derived are listed in Tables 1A and 1B. Unless otherwise specified, all assays were performed in triplicate and results were obtained in at least three independent experiments.…”

Targeting cholesterol homeostasis in hematopoietic malignancies

“…Cholesterol biosynthesis is transcriptionally induced in AML cells under hypoxic stress conditions and attenuated by cytarabine and quizartinib, the latter being a selective inhibitor of class III receptor tyrosine kinases, including FMS-related tyrosine kinase 3. 37 Interestingly, cytarabine increases intracellular cholesterol content in AML cells independently of O 2 tension, possibly switching to scavenger mode through the upregulation of CD36. In this setting, rosuvastatin exerts a significant antileukemic activity against a wide variety of AML cells and acts synergistically with cytarabine at different levels of O 2 , an observation deserving investigation of rosuvastatin-based therapies to target residual AML cells that reside in low-O 2 environments, such as the leukemic niche.…”