DOT1L inhibition is lethal for multiple myeloma due to perturbation of the endoplasmic reticulum stress pathway

// Caroline Dafflon 1 , Swann Gaulis 1 , Louise Barys 1 , Karen Kapur 2 , Vanessa Cornacchione 3 , Lina Schukur 1 , Sebastian Bergling 4 , Elisabetta Traggiai 3 , Selina Jansky 1 , Leon Hellmann 1 , Barbara Schacher Engstler 1 , Grainne Kerr 1 , Antoine de Weck 1 , David A. Ruddy 5 , Ulrike Naumann 6 , Frederic Stauffer 7 , Christoph Gaul 7 , Ying Lin 8 , Eric Billy 1 , Andreas Weiss 1 , Francesco Hofmann 1 , Moriko Ito 1 and Ralph Tiedt 1 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 Correspondence to: Ralph Tiedt, email: ralph.tiedt@novartis.com Keywords: DOT1L; multiple myeloma; epigenetics; histone methylation; unfolded protein response Received: June 17, 2019     Accepted: January 29, 2020     Published: March 17, 2020 ABSTRACT 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.