NTHU research team develops new treatment for Parkinson’s disease
The sensitivity of MM cells to proteasome inhibitors is thought to be due to perturbation of the hyperactive UPR, which may offer some degree of selectivity versus non-cancerous cells.
Through pharmacologic and genetic approaches, we found that inhibition of DOT1L, an H3K79 methyltransferase, profoundly reduces the viability of a subset of MM cell lines in vitro and inhibits the growth of established MM xenografts in mice.
CRISPR screens further revealed that targeting the histone methyltransferase SETD1B concomitantly with DOT1L further enhances this effect on the UPR and increases and accelerates MM cell death.
The Tiedt Research Team concluded in their Oncotarget Research Paper, "our discovery indicates a novel opportunity for DOT1L inhibitors in cancer treatment. Concomitant targeting of SETD1B enhances phenotypic and transcriptional effects of DOT1L inhibition in sensitive MM cell lines, which may be an additional therapeutic angle. To our knowledge, no selective SETD1B inhibitors have been described yet, and our data questions whether its methyltransferase activity is critical in the MM context. Additional work is needed to address this question and guide drug discovery." Source:
Oncotarget Journal reference:
Dafflon, C., et al. (2020) DOT1L inhibition is lethal for multiple myeloma due to perturbation of the endoplasmic reticulum stress pathway. Oncotarget . doi.org/10.18632/oncotarget.27493 .
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