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Targeting the metabolic vulnerability of acute myeloid leukemia blasts with a combination of venetoclax and 8-chloro-adenosine

ABSTRACT: Purpose: To show that 8-Cl-Ado can target FAO and synergizes with VEN to significantly decrease the oxygen consumption rate (OCR) and in turn OXPHOS in CD34-enriched AML cells. Methods: Using AML cell lines and LSC-enriched blast cells from pre-treatment AML patients, we evaluated the effects of 8-Cl-Ado, VEN and the 8-Cl-Ado/VEN combination on fatty acid metabolism, glycolysis and OXPHOS using liquid scintillation counting, a Seahorse XF Analyzer and gene set enrichment analysis (GSEA). Results: We here report that VEN and 8-Cl-Ado synergistically inhibited in vitro growth of AML cells. Furthermore, immunodeficient mice engrafted with MV4-11-Luc AML cells and treated with the combination of VEN plus 8-Cl-Ado had a significantly longer survival than mice treated with either drugs alone (p≤0.006). Conclusion: Taken together, the results suggest that 8-Cl-Ado enhances the antileukemic activity of VEN and that this combination represents a promising therapeutic regimen for treatment of AML.

ORGANISM(S): Homo sapiens

PROVIDER: GSE171552 | GEO | 2021/04/07

REPOSITORIES: GEO

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AML patients for in vivo study of venetoclax plus AraC treatment

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Fatty acid metabolism mediates venetoclax resistance in acute myeloid leukemia stem cells

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Fatty acid metabolism mediates venetoclax resistance in acute myeloid leukemia stem cells

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miRNA-1 promotes Acute Myeloid Leukemia cell pathogenesis through metabolic regulation [miRNA]

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