DOT1L inhibition is lethal for multiple myeloma due to perturbation of the endoplasmic reticulum stress pathway
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Caroline Dafflon1, Swann Gaulis1, Louise Barys1, Karen Kapur2, Vanessa Cornacchione3, Lina Schukur1, Sebastian Bergling4, Elisabetta Traggiai3, Selina Jansky1, Leon Hellmann1, Barbara Schacher Engstler1, Grainne Kerr1, Antoine de Weck1, David A. Ruddy5, Ulrike Naumann6, Frédéric Stauffer7, Christoph Gaul7, Ying Lin8, Eric Billy1, Andreas Weiss1, Francesco Hofmann1, Moriko Ito1 and Ralph Tiedt1
1 Novartis Institutes for BioMedical Research (NIBR) Oncology, Basel, Switzerland
2 NIBR Informatics, Basel, Switzerland
3 NIBR Biologics, Basel, Switzerland
4 NIBR Chemical Biology and Therapeutics, Basel, Switzerland
5 NIBR Oncology, Cambridge, MA, USA
6 NIBR Analytical Sciences and Imaging, Basel, Switzerland
7 NIBR Global Discovery Chemistry, Basel, Switzerland
8 China Novartis Institutes for BioMedical Research, Shanghai, China
Keywords: DOT1L; multiple myeloma; epigenetics; histone methylation; unfolded protein response
Received: June 17, 2019 Accepted: January 29, 2020 Published: March 17, 2020
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.
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