title: PTTG1 expression is associated with hyperproliferative disease and poor prognosis in multiple myeloma.
abstract: BACKGROUND
  Multiple myeloma (MM) is an incurable haematological malignancy characterised by the clonal proliferation of malignant plasma cells within the bone marrow. We have previously identified pituitary tumour transforming gene 1 (Pttg1) as a gene that is significantly upregulated in the haematopoietic compartment of the myeloma-susceptible C57BL/KaLwRij mouse strain, when compared with the myeloma-resistant C57BL/6 mouse. Over-expression of PTTG1 has previously been associated with malignant progression and an enhanced proliferative capacity in solid tumours.
  
  
  METHODS
  In this study, we investigated PTTG1 gene and protein expression in MM plasma cells from newly diagnosed MM patients. Gene expression profiling was used to identify gene signatures associated with high PTTG1 expression in MM patients. Additionally, we investigated the effect of short hairpin ribonucleic acid (shRNA)-mediated PTTG1 knockdown on the proliferation of the murine myeloma plasma cell line 5TGM1 in vitro and in vivo.
  
  
  RESULTS
  PTTG1 was found to be over-expressed in 36-70 % of MM patients, relative to normal controls, with high PTTG1 expression being associated with poor patient outcomes (hazard ratio 2.49; 95 % CI 1.28 to 4.86; p = 0.0075; log-rank test). In addition, patients with high PTTG1 expression exhibited increased expression of cell proliferation-associated genes including CCNB1, CCNB2, CDK1, AURKA, BIRC5 and DEPDC1. Knockdown of Pttg1 in 5TGM1 cells decreased cellular proliferation, without affecting cell cycle distribution or viability, and decreased expression of Ccnb1, Birc5 and Depdc1 in vitro. Notably, Pttg1 knockdown significantly reduced MM tumour development in vivo, with an 83.2 % reduction in tumour burden at 4 weeks (p < 0.0001, two-way ANOVA).
  
  
  CONCLUSIONS
  This study supports a role for increased PTTG1 expression in augmenting tumour development in a subset of MM patients.
authors.affiliation: Myeloma Research Laboratory, Department of Physiology, School of Medicine, Faculty of Health Sciences, University of Adelaide and Cancer Theme, South Australian Health and Medical Research Institute (SAHMRI), Adelaide, Australia. Jacqueline.Noll@adelaide.edu.aul.
authors.forename: Jacqueline E
authors.initials: JE
authors.lastname: Noll
authors.affiliation: Myeloma Research Laboratory, Department of Physiology, School of Medicine, Faculty of Health Sciences, University of Adelaide and Cancer Theme, South Australian Health and Medical Research Institute (SAHMRI), Adelaide, Australia. Kate.Vandyke@adelaide.edu.au.|SA Pathology, Adelaide, Australia. Kate.Vandyke@adelaide.edu.au.
authors.forename: Kate
authors.initials: K
authors.lastname: Vandyke
authors.affiliation: Myeloma Research Laboratory, Department of Physiology, School of Medicine, Faculty of Health Sciences, University of Adelaide and Cancer Theme, South Australian Health and Medical Research Institute (SAHMRI), Adelaide, Australia. Duncan.Hewett@adelaide.edu.au.
authors.forename: Duncan R
authors.initials: DR
authors.lastname: Hewett
authors.affiliation: Myeloma Research Laboratory, Department of Physiology, School of Medicine, Faculty of Health Sciences, University of Adelaide and Cancer Theme, South Australian Health and Medical Research Institute (SAHMRI), Adelaide, Australia. Krzysztof.Mrozik@adelaide.edu.au.
authors.forename: Krzysztof M
authors.initials: KM
authors.lastname: Mrozik
authors.affiliation: Myeloma Research Laboratory, Department of Physiology, School of Medicine, Faculty of Health Sciences, University of Adelaide and Cancer Theme, South Australian Health and Medical Research Institute (SAHMRI), Adelaide, Australia. Rachel.Bala@health.sa.gov.au.
authors.forename: Rachel J
authors.initials: RJ
authors.lastname: Bala
authors.affiliation: Myeloma Research Laboratory, Department of Physiology, School of Medicine, Faculty of Health Sciences, University of Adelaide and Cancer Theme, South Australian Health and Medical Research Institute (SAHMRI), Adelaide, Australia. Sharondotwilliams@gmail.com.
authors.forename: Sharon A
authors.initials: SA
authors.lastname: Williams
authors.affiliation: Leukaemia Research Group, Cancer Theme, SAHMRI, Adelaide, Australia. Chung.Kok@sahmri.com.
authors.forename: Chung H
authors.initials: CH
authors.lastname: Kok
authors.affiliation: Myeloma Research Laboratory, Department of Physiology, School of Medicine, Faculty of Health Sciences, University of Adelaide and Cancer Theme, South Australian Health and Medical Research Institute (SAHMRI), Adelaide, Australia. Andrew.Zannettino@adelaide.edu.au.|Discipline of Physiology, School of Medicine, Faculty of Health Sciences, University of Adelaide, Cancer Theme, Level 5 South, SAHMRI, PO Box 11060, Adelaide, SA, 5001, Australia. Andrew.Zannettino@adelaide.edu.au.
authors.forename: Andrew Cw
authors.initials: AC
authors.lastname: Zannettino
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002453:Cell Cycle / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D008297:Male; D008810:Mice, Inbred C57BL; D018613:Microscopy, Confocal; D009101:Multiple Myeloma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009374:Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D010950:Plasma Cells / Q000378:metabolism / Q000473:pathology; D011379:Prognosis; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D064249:Securin / Q000235:genetics* / Q000378:metabolism; D016019:Survival Analysis; D047368:Tumor Burden / Q000235:genetics
chemical_list: D064249:Securin; C578002:pituitary tumor-transforming protein 1, human