DOT1L inhibition is lethal for multiple myeloma due to perturbation of the endoplasmic reticulum stress pathway
| Autor: | Swann Gaulis, Lina Schukur, Leon Hellmann, Vanessa Cornacchione, Ulrike Naumann, Christoph Gaul, Ralph Tiedt, Francesco Hofmann, Louise Barys, Eric Billy, Elisabetta Traggiai, Sebastian Bergling, Moriko Ito, Ying Lin, Antoine de Weck, Grainne Kerr, Barbara Schacher Engstler, David A. Ruddy, Selina Jansky, Caroline Dafflon, Andreas Weiss, Frédéric Stauffer, Karen Kapur |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Methyltransferase epigenetics Chemistry Endoplasmic reticulum DOT1L unfolded protein response Cell biology multiple myeloma 03 medical and health sciences 030104 developmental biology 0302 clinical medicine Oncology Cell culture 030220 oncology & carcinogenesis Gene expression Histone methylation Unfolded protein response H3K4me3 histone methylation Research Paper |
| Zdroj: | Oncotarget |
| ISSN: | 1949-2553 |
| Popis: | The histone 3 lysine 79 (H3K79) methyltransferase (HMT) DOT1L is known to play a critical role for growth and survival of MLL-rearranged leukemia. Serendipitous observations during high-throughput drug screens indicated that the use of DOT1L inhibitors might be expandable to multiple myeloma (MM). Through pharmacologic and genetic experiments, we could validate that DOT1L is essential for growth and viability of a subset of MM cell lines, in line with a recent report from another team. In vivo activity against established MM xenografts was observed with a novel DOT1L inhibitor. In order to understand the molecular mechanism of the dependency in MM, we examined gene expression changes upon DOT1L inhibition in sensitive and insensitive cell lines and discovered that genes belonging to the endoplasmic reticulum (ER) stress pathway and protein synthesis machinery were specifically suppressed in sensitive cells. Whole-genome CRISPR screens in the presence or absence of a DOT1L inhibitor revealed that concomitant targeting of the H3K4me3 methyltransferase SETD1B increases the effect of DOT1L inhibition. Our results provide a strong basis for further investigating DOT1L and SETD1B as targets in MM. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
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