Abstract 2986: Study of genetic dependencies associated with 1q-amplified multiple myeloma
Authors: Reidy Mairead , Sklavenitis-Pistofidis Romanos , Huynh Daisy , Salem Karma Ziad , Park Jihye , Glavey Siobhan , Manier Salomon , Ghobrial Irene 
Published: August 2019

Multiple myeloma is a malignancy of terminally differentiated plasma cells with a strikingly heterogeneous genomic landscape. Genetic alterations including t(4;14), and t(14;16) translocations alongside amplification of chromosome 1q21 are particularly associated with a poor outcome. Amplification of the long arm of chromosome 1 (1q) is among the most frequent copy number alterations encountered, with a confirmed adverse effect on survival. Gene expression profiling has identified a minimal common amplified region between 1q21 and 1q23 as a probable target of the amplification event, however the actionable gene dependencies in that region have not been explored. In this study, we employ a large number of inhouse and publicly available CRISPR, shRNA and drug screens in an effort to characterize the genetic dependencies of 1q-amplified myeloma and discover drugs that target them. Ultimately, we hope to propose a tailored therapeutic strategy for patients with 1q-amplified multiple myeloma.

We employed a combination of publicly available (Project Achilles, Dependency Map) and in-house CRISPR and RNAi screens to identify differential dependencies of 1q+ MM. All data were pre-processed and analyzed consistently. Genes were filtered for evidence of both differential dependency and differential expression in 1q+ cell lines. A frequentist approach, prioritizing genes by the number of datasets they hit in, was combined with a gene-wise weighted linear model approach. Genes that hit in at least two datasets and were confirmed by the linear model were taken into consideration for Hallmark pathway analysis with GSEA. Cell cycle, c-Myc, mTOR/PI3K, DNA repair, p53, protein secretion and degradation all constitute major addictions in 1q+ MM and suggest differential sensitivity to corresponding compounds.

We searched for differential drug sensitivities utilizing the Drug Repurposing Library as well as a CMap-guided screen. We identified as hits several compounds targeting both the ubiquitin and the cell cycle pathway, including PI3 kinase, PARP, NAMPT and GSK-3 inhibitors which act primarily through a G2/M block thus validating the dependencies discovered in our datasets.

In conclusion, here we employed a combination of multiple in-house and publicly available CRISPR, shRNA and drug screens, in the largest to date effort to characterize and target the genetic dependencies of 1q-amplified multiple myeloma. Cell cycle and the ubiquitin pathway came up as strong dependencies, while the drugs that target them were indeed shown to preferentially kill 1q-amplified myeloma cell lines. Thus, for the first time, our results suggest that patients with 1q-amplified myeloma might benefit from genetically tailored treatment involving cell cycle and ubiquitin inhibitors or a combination. As 1q amplification is one of myeloma’s few frequent alterations, this discovery has the exciting potential to affect change in a large number of patients.

Citation Format: Mairead Reidy, Romanos Sklavenitis-Pistofidis, Daisy Huynh, Karma Ziad Salem, Jihye Park, Siobhan Glavey, Salomon Manier, Irene Ghobrial. Study of genetic dependencies associated with 1q-amplified multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2986.