Abstract
BackgroundMultiple 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.MethodsIn 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.ResultsPTTG1 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).ConclusionsThis study supports a role for increased PTTG1 expression in augmenting tumour development in a subset of MM patients.Electronic supplementary materialThe online version of this article (doi:10.1186/s13045-015-0209-2) contains supplementary material, which is available to authorized users.
Highlights
Multiple myeloma (MM) is an incurable haematological malignancy characterised by the clonal proliferation of malignant plasma cells within the bone marrow
PTTG1 is over-expressed in the C57BL/KaLwRij mouse model of myeloma In order to identify genes that may play a role in the development of myeloma, we previously compared the transcriptome of the bone/bone marrow (BM) of KaLwRij mice to that of the genetically related C57BL/6 strain using microarray [15]
Studies have identified a role for PTTG1 in regulating epithelial-mesenchymal transition (EMT) [79,80,81] and recent studies by Azab and colleagues [82] have identified a role for the EMT processes in the dissemination and homing of MM plasma cells to the BM, we showed no association between the expression of EMT-related genes and high PTTG1 expression in MM patients
Summary
Multiple myeloma (MM) is an incurable haematological malignancy characterised by the clonal proliferation of malignant plasma cells within the bone marrow. The introduction of novel therapies has seen a significant improvement in the median survival of some groups of MM patients, the survival for some subgroups of patients, those with highly proliferative disease, remains poor [7]. This highlights the need to identify new genes and pathways that may be involved in the pathophysiology of MM to aid in both prognosis and the development of novel therapeutics
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