Abstract
Treatment regimens for acute myeloid leukemia (AML) continue to offer weak clinical outcomes. Through a high-throughput cell-based screen, we identified avocatin B, a lipid derived from avocado fruit, as a novel compound with cytotoxic activity in AML. Avocatin B reduced human primary AML cell viability without effect on normal peripheral blood stem cells. Functional stem cell assays demonstrated selectivity toward AML progenitor and stem cells without effects on normal hematopoietic stem cells. Mechanistic investigations indicated that cytotoxicity relied on mitochondrial localization, as cells lacking functional mitochondria or CPT1, the enzyme that facilitates mitochondria lipid transport, were insensitive to avocatin B. Furthermore, avocatin B inhibited fatty acid oxidation and decreased NADPH levels, resulting in ROS-dependent leukemia cell death characterized by the release of mitochondrial proteins, apoptosis-inducing factor, and cytochrome c. This study reveals a novel strategy for selective leukemia cell eradication based on a specific difference in mitochondrial function.
Highlights
Leukemia and leukemia stem cells (LSC) possess several mitochondrial features that distinguish them from normal hematopoietic cells
Avocatin B's selectivity toward leukemia cells was validated in primary Acute myeloid leukemia (AML) samples and in peripheral blood stem cells (PBSC) isolated from G-CSF–stimulated healthy donors
Because avocatin B contains 17-carbon lipids and lipids of that size can enter the mitochondria and undergo fatty acid oxidation after they have been processed by carnitine palmitoyltransferase 1 (CPT1), we evaluated the impact of avocatin B on fatty acid oxidation
Summary
Leukemia and leukemia stem cells (LSC) possess several mitochondrial features that distinguish them from normal hematopoietic cells. Leukemia cells contain greater mitochondrial mass, have higher rates of oxidative phosphorylation [1], and depend on fatty acid oxidation for survival [2]. Together, these altered mitochondrial characteristics may make drugs that target mitochondria potentially useful for the eradication of leukemia cells. Acute myeloid leukemia (AML) is a devastating disease characterized by the accumulation of malignant myeloid precursors that fail to terminally differentiate [3]. Patients diagnosed with AML are faced with poor disease prognosis.
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