The sumoylation pathway is dysregulated in multiple myeloma and is associated with adverse patient outcome

James J. Driscoll, Dheeraj Pelluru, Konstantinos Lefkimmiatis, Mariateresa Fulciniti, Rao H. Prabhala, Philip R. Greipp, Bart Barlogie, Yu Tzu Tai, Kenneth C. Anderson, John D. Shaughnessy, Christina M. Annunziata, Nikhil C. Munshi

Research output: Contribution to journalArticlepeer-review

90 Scopus citations

Abstract

Multiple myeloma (MM) is a plasma cell neoplasm that proceeds through a premalignant state of monoclonal gammopathy of unknown significance; however, the molecular events responsible for myelomagenesis remain uncharacterized. To identify cellular pathways deregulated in MM, we addressed that sumoylation is homologous to ubiquitination and results in the attachment of the ubiquitin-like protein Sumo onto target proteins. Sumoylation was markedly enhanced in MM patient lysates compared with normal plasma cells and expression profiling indicated a relative induction of sumoylation pathway genes. The Sumoconjugating enzyme Ube2I, the Sumoligase PIAS1, and the Sumo-inducer ARF were elevated in MM patient samples and cell lines. Survival correlated with expression because 80% of patients with low UBE2I and PIAS1 were living 6 years after transplantation, whereas only 45% of patients with high expression survived 6 years. UBE2I encodes the sole Sumo-conjugating enzyme in mammalian cells and cells transfected with a dominant-negative sumoylation-deficient UBE2I mutant exhibited decreased survival after radiation exposure, impaired adhesion to bone marrow stroma cell and decreased bone marrow stroma cell-induced proliferation. UBE2I confers cells with multiple advantages to promote tumorigenesis and predicts decreased survival when combined with PIAS1. The sumoylation pathway is a novel therapeutic target with implications for existing proteasomal-based treatment strategies.

Original languageEnglish
Pages (from-to)2827-2834
Number of pages8
JournalBlood
Volume115
Issue number14
DOIs
StatePublished - 8 Apr 2010
Externally publishedYes

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