title: MAGE-A inhibits apoptosis in proliferating myeloma cells through repression of Bax and maintenance of survivin.
abstract: OBJECTIVE
  The type I Melanoma Antigen GEnes (MAGEs) are commonly expressed in cancers, fueling speculation that they may be therapeutic targets with oncogenic potential. They form complexes with RING domain proteins that have E3 ubiquitin ligase activity and promote p53 degradation. MAGE-A3 was detected in tumor specimens from patients with multiple myeloma and its expression correlated with higher frequencies of Ki-67(+) malignant cells. In this report, we examine the mechanistic role of MAGE-A in promoting survival of proliferating multiple myeloma cells.
  
  
  METHODS
  The impact of MAGE-A3 expression on survival and proliferation in vivo was examined by immunohistochemical analysis in an independent set of tumor specimens segregated into two groups: newly diagnosed, untreated patients and patients who had relapsed after chemotherapy. The mechanisms of MAGE-A3 activity were investigated in vitro by silencing its expression by short hairpin RNA interference in myeloma cell lines and primary cells and assessing the resultant effects on proliferation and apoptosis.
  
  
  RESULTS
  MAGE-A3 was detected in a significantly higher percentage of relapsed patients compared with newly diagnosed, establishing a novel correlation with progression of disease. Silencing of MAGE-A showed that it was dispensable for cell cycling, but was required for survival of proliferating myeloma cells. Loss of MAGE-A led to apoptosis mediated by p53-dependent activation of proapoptotic Bax expression and by reduction of survivin expression through both p53-dependent and -independent mechanisms.
  
  
  CONCLUSIONS
  These data support a role for MAGE-A in the pathogenesis and progression of multiple myeloma by inhibiting apoptosis in proliferating myeloma cells through two novel mechanisms.
authors.affiliation: New York University Cancer Institute, New York University School of Medicine, New York, New York, USA.
authors.forename: Tricia
authors.initials: T
authors.lastname: Nardiello
authors.forename: Achim A
authors.initials: AA
authors.lastname: Jungbluth
authors.forename: Anna
authors.initials: A
authors.lastname: Mei
authors.forename: Maurizio
authors.initials: M
authors.lastname: Diliberto
authors.forename: Xiangao
authors.initials: X
authors.lastname: Huang
authors.forename: Ania
authors.initials: A
authors.lastname: Dabrowski
authors.forename: Valéria C C
authors.initials: VC
authors.lastname: Andrade
authors.forename: Rebecca
authors.initials: R
authors.lastname: Wasserstrum
authors.forename: Scott
authors.initials: S
authors.lastname: Ely
authors.forename: Ruben
authors.initials: R
authors.lastname: Niesvizky
authors.forename: Roger
authors.initials: R
authors.lastname: Pearse
authors.forename: Morton
authors.initials: M
authors.lastname: Coleman
authors.forename: David S
authors.initials: DS
authors.lastname: Jayabalan
authors.forename: Nina
authors.initials: N
authors.lastname: Bhardwaj
authors.forename: Lloyd J
authors.initials: LJ
authors.lastname: Old
authors.forename: Selina
authors.initials: S
authors.lastname: Chen-Kiang
authors.forename: Hearn Jay
authors.initials: HJ
authors.lastname: Cho
mesh_terms: D000951:Antigens, Neoplasm / Q000235:genetics / Q000378:metabolism*; D017209:Apoptosis / Q000235:genetics; D002453:Cell Cycle / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018450:Disease Progression; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D000077022:Survivin; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism*
chemical_list: D000951:Antigens, Neoplasm; C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; C072013:MAGEA3 protein, human; D009363:Neoplasm Proteins; D000077022:Survivin; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein