Extensive epidemiological data have demonstrated an exponential rise in the incidence of non-Hodgkin lymphoma (NHL) that is associated with increasing age. The molecular etiology of this remains largely unknown, which impacts the effectiveness of treatment for patients. A team led by researchers from University of Massachusetts Medical School  proposed that age-dependent circulating microRNA (miRNA) signatures in the host influence diffuse large B cell lymphoma (DLBCL) development. The objective of their recent study was to examine tumor development in an age-based DLBCL system using an inventive systems biology approach.

Researchers harnessed a novel murine model of spontaneous DLBCL initiation (Smurf2-deficient) at two age groups: 3 and 15 months old. All Smurf2-deficient mice developed visible DLBCL tumor starting at 15 months of age. Total miRNA was isolated from serum, bone marrow and spleen and collected for all age groups for Smurf2-deficient mice and age-matched wild-type C57BL/6 mice. Using systems biology techniques and miRNA microarrays, they identified a list of 10 circulating miRNAs being regulated in both the spleen and bone marrow that were present in DLBCL forming mice starting at 3 months of age that were not present in the control mice.

 

Circulating miRNA signature from the serum of 3-month old mice comparing Smurf2T/T to wild type mice

journal.pone.0170521.g002

miRNA was quantified by ddPCR and exact miRNA copies/nanogram of serum was measured. The data is shown as both a heatmap of miRNA copies/nanogram for each mouse and the average counts (bar plots). The error bars in the bar plots represents the standard error. The color gradient for the heatmap represents the miRNA copies/nanogram which is shown as different colors in the hearmap.

Furthermore, this miRNA signature was found to occur circulating in the blood and it strongly impacted JUN and MYC oncogenic signaling. In addition, quantification of the miRNA signature was performed via Droplet Digital PCR technology. It was discovered that a key miRNA signature circulates throughout a host prior to the formation of a tumor starting at 3 months old, which becomes further modulated by age and yielded calculation of a ‘carcinogenic risk score’.

This novel age-based circulating miRNA signature may potentially be leveraged as a DLBCL risk profile at a young age to predict future lymphoma development or disease progression as well as for potential innovative miRNA-based targeted therapeutic strategies in lymphoma.

 

Reference
A. Beheshti, C. Vanderburg, J. T. McDonald, C. Ramkumar, T. Kadungure, H. Zhang, R. B. Gartenhaus, A. M. Evens (2016) A Circulating microRNA Signature Predicts Age-Based Development of Lymphoma PLoS ONE 12(1): e0170521. doi: 10.1371/journal.pone.0170521 [article]

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