The sumoylation pathway is dysregulated in multiple myeloma and is associated with adverse patient outcome.
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 Sumo-conjugating enzyme Ube2I, the Sumo-ligase 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.
Driscoll
James J
JJ
Department of Research, Veterans Administration Boston Healthcare, West Roxbury, MA, USA. driscollj@mail.nih.gov
Pelluru
Dheeraj
D
Lefkimmiatis
Konstantinos
K
Fulciniti
Mariateresa
M
Prabhala
Rao H
RH
Greipp
Philip R
PR
Barlogie
Bart
B
Tai
Yu-Tzu
YT
Anderson
Kenneth C
KC
Shaughnessy
John D
JD
Annunziata
Christina M
CM
Munshi
Nikhil C
NC
D001854:Bone Marrow Cells / Q000378:metabolism; D002448:Cell Adhesion / Q000235:genetics; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics; D018572:Disease-Free Survival; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D008297:Male; D009101:Multiple Myeloma / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000628:therapy; D009154:Mutation; D010950:Plasma Cells / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism; D050828:Protein Inhibitors of Activated STAT / Q000096:biosynthesis; D011499:Protein Processing, Post-Translational; D025842:SUMO-1 Protein / Q000235:genetics / Q000378:metabolism*; D025841:Small Ubiquitin-Related Modifier Proteins / Q000096:biosynthesis; D033581:Stem Cell Transplantation; D017154:Stromal Cells / Q000378:metabolism; D014184:Transplantation, Homologous; D044763:Ubiquitin-Conjugating Enzymes / Q000096:biosynthesis; D000098843:Ubiquitin-Conjugating Enzyme UBC9
C106529:PIAS1 protein, human; D050828:Protein Inhibitors of Activated STAT; D025842:SUMO-1 Protein; D025841:Small Ubiquitin-Related Modifier Proteins; D044763:Ubiquitin-Conjugating Enzymes; D046988:Proteasome Endopeptidase Complex; D000098843:Ubiquitin-Conjugating Enzyme UBC9