Identification of molecular vulnerabilities in human multiple myeloma cells by RNA interference lethality screening of the druggable genome.

Abstract

Despite recent advances in targeted treatments for multiple myeloma, optimal molecular therapeutic targets have yet to be identified. To functionally identify critical molecular targets, we conducted a genome-scale lethality study in multiple myeloma cells using siRNAs. We validated the top 160 lethal hits with four siRNAs per gene in three multiple myeloma cell lines and two non-myeloma cell lines, cataloging a total of 57 potent multiple myeloma survival genes. We identified the Bcl2 family member MCL1 and several 26S proteasome subunits among the most important and selective multiple myeloma survival genes. These results provided biologic validation of our screening strategy. Other essential targets included genes involved in RNA splicing, ubiquitination, transcription, translation, and mitosis. Several of the multiple myeloma survival genes, especially MCL1, TNK2, CDK11, and WBSCR22, exhibited differential expression in primary plasma cells compared with other human primary somatic tissues. Overall, the most striking differential functional vulnerabilities between multiple myeloma and non-multiple myeloma cells were found to occur within the 20S proteasome subunits, MCL1, RRM1, USP8, and CKAP5. We propose that these genes should be investigated further as potential therapeutic targets in multiple myeloma.

• Authors: Rodger E Tiedemann, Yuan Xao Zhu, Jessica Schmidt, Chang Xin Shi, Chris Sereduk, Hongwei Yin, Spyro Mousses, A Keith Stewart
• Journal: Cancer research (Cancer Res) Vol. 72 Issue 3 Pg. 757-68 (Feb 01 2012) ISSN: 1538-7445 [Electronic] United States
• PMID: 22147262 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2011 AACR.

Chemical References

• Antineoplastic Agents
• Biomarkers, Tumor
• Myeloid Cell Leukemia Sequence 1 Protein
• Proto-Oncogene Proteins c-bcl-2
• BUD23 protein, human
• Methyltransferases
• Protein-Tyrosine Kinases
• TNK2 protein, human
• CDK11a protein, human
• Cyclin-Dependent Kinases

Topics

• Antineoplastic Agents (pharmacology)
• Biomarkers, Tumor (genetics)
• Cell Line, Tumor
• Cell Survival (drug effects, genetics)
• Cyclin-Dependent Kinases (genetics)
• Gene Expression Profiling
• Gene Expression Regulation, Neoplastic
• Genes, Lethal (genetics)
• Genetic Predisposition to Disease (genetics)
• Genome, Human (genetics)
• HEK293 Cells
• Humans
• Methyltransferases (genetics)
• Multiple Myeloma (drug therapy, genetics, pathology)
• Myeloid Cell Leukemia Sequence 1 Protein
• Protein-Tyrosine Kinases (genetics)
• Proto-Oncogene Proteins c-bcl-2 (genetics)
• RNA Interference