TY - JOUR
T1 - The sumoylation pathway is dysregulated in multiple myeloma and is associated with adverse patient outcome
AU - Driscoll, James J.
AU - Pelluru, Dheeraj
AU - Lefkimmiatis, Konstantinos
AU - Fulciniti, Mariateresa
AU - Prabhala, Rao H.
AU - Greipp, Philip R.
AU - Barlogie, Bart
AU - Tai, Yu Tzu
AU - Anderson, Kenneth C.
AU - Shaughnessy, John D.
AU - Annunziata, Christina M.
AU - Munshi, Nikhil C.
PY - 2010/4/8
Y1 - 2010/4/8
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=77951010059&partnerID=8YFLogxK
U2 - 10.1182/blood-2009-03-211045
DO - 10.1182/blood-2009-03-211045
M3 - Article
C2 - 19965618
AN - SCOPUS:77951010059
SN - 0006-4971
VL - 115
SP - 2827
EP - 2834
JO - Blood
JF - Blood
IS - 14
ER -