Overexpression of Gene Leads to Poor Survival in Multiple Myeloma Patients

Multiple myeloma disease development affected by pituitary tumor transforming gene.

Multiple myeloma disease development affected by pituitary tumor transforming gene.

Multiple myeloma (MM) is a dangerous disease characterized by the production of daughter malignant plasma cells within the bone marrow.

Previous studies have identified pituitary tumor transforming gene 1 (Pttg1) as significantly over-expressed in the hematopoietic compartment of a myeloma-susceptible mouse strain, when compared with the myeloma-resistant mouse. This upregulation has been associated with malignant progression and enhanced proliferative capacity in solid tumors.

Higher levels of PTTG1 has previously been linked to neoplastic transformation in a wide range of cell types. While much has been studied in increased expression of PTTG1 in pituitary adenomas and other endocrine cancers, little is known about the role of PTTG1 in hematological malignancies.

Previous studies have indicated that PTTG1 was highly expressed in approximately 70% of patients with leukemia, lymphoma, or other myelodysplastic diseases but not in healthy donors.

Higher levels of PTTG1 have also been noted in 63% of MM patients; however, the biological and prognostic significance of PTTG1 over-expression was not investigated in these studies.

The current study investigated PTTG1 gene and protein expression in MM plasma cells from newly diagnosed patients with the disease.

Scientists performed in silico analyses in 3 independent publically available microarray datasets to examine whether MM patients display increased PTTG1 expression.

The findings showed that approximately 38 to 70% of MM patients expressed PTTG1 at higher levels than what are considered to be normal range.

The scientists next compared MM plasma cell gene expression between PTTG1 high and PTTG1 low MM patients in 4 independent microarray datasets. There were 29 genes found to be significantly under-expressed, and 1459 genes found to be over-expressed in at least one dataset.

Of these, 155 genes were significantly up-regulated, and no genes were down-regulated in all 4 datasets. Genes that were over-expressed by more than twice the normal range all with a strong positive correlation with PTTG1 expression included key cell cycle regulators, genes associated with DNA replication, and response to DNA damage.

Additionally, the analyses show that PTTG1 is over-expressed in MM patients, but not in the asymptomatic precursor MGUS, which suggests the association comes with disease progression.

To summarize, the study identified PTTG1 as a gene whose over-expression in MM patients with hyperdiploidy or with hyeproliferative disease suggests a role in MM disease development.

It is the first study to show that PTTG1 expression alone is sufficient to identify a subset of patients with poor overall survival.

“Collectively, our data suggest that the poor prognosis associated with PTTG1 expression is due to a hyperproliferative state in these patients, which may result from the PTTG1-mediated upregulation of key drivers of cell cycle progression,” the study authors concluded.