15‐Methylene‐Eburnamonine Kills Leukemic Stem Cells and Reduces Engraftment in a Humanized Bone Marrow Xenograft Mouse Model of Leukemia

Abstract

Recent studies suggest that leukemia stem cells (LSCs) play a critical role in initiation, propagation, and relapse of leukemia. Herein we show that (−)-15-methylene-eburnamonine, a derivative of the alkaloid, (−)-eburnamonine, is cytotoxic against acute and chronic lymphocytic leukemias (ALL and CLL) and acute myelogenous leukemia (AML). The agent also reduces primary LSC frequency in vitro. The cytotoxic effects appear to be mediated via the oxidative stress pathways. Furthermore, we show that the compound kills AML, ALL, and CLL stem cells, and using a novel humanized bone marrow murine model of leukemia (huBM/NSG), it reduces progenitor cell engraftment.