Dihydroartemisinin inhibits the proliferation of multiple myeloma cancer stem cells via disturbing nuclear lamina and chromatin architecture

We establish a method to reprogram bulk multiple myeloma (MM) cancer cells into MM cancer stem cells (MMSCs) via heterochromatin modulation, which allows us to obtain sufficient functional MMSCs in an efficient manner. Characterization of these induced MMSCs demonstrates that the reprogrammed MMSCs possess the properties of cancer stem cells both phenotypically and functionally. To leverage this model therapeutically, we screened a panel of compounds, and identified dihydroartemisinin (DHA) as a potent anti-MMSCs drug both in vitro and in vivo. DHA induces anti-proliferation effects on MMSCs via nuclear lamina perturbation and chromatin structure alteration. Hi-C analysis reveals that DHA modulates chromatin architecture mainly at the compartmental level and TADs (topologically associating domains) level. The potent anti-MMSCs efficacy and the novel molecular insights establish the therapeutic rationale for DHA in overcoming therapy resistance caused by cancer stem cells. Overall design: 1.Global transcriptional profiles of the reprogrammed MMSCs and their parental cells;2.Efect of dihydroartemisinin on the global transcriptional profiles of the reprogrammed MMSCs(U266-CSCs)