Date Published: January 20, 2017
Publisher: Public Library of Science
Author(s): Afshin Beheshti, Charles Vanderburg, J. Tyson McDonald, Charusheila Ramkumar, Tatenda Kadungure, Hong Zhang, Ronald B. Gartenhaus, Andrew M. Evens, Jianjun Zhao.
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. We proposed that age-dependent circulating microRNA (miRNA) signatures in the host influence diffuse large B cell lymphoma (DLBCL) development. Our objective was to examine tumor development in an age-based DLBCL system using an inventive systems biology approach. We harnessed a novel murine model of spontaneous DLBCL initiation (Smurf2-deficient) at two age groups: 3 and 15 months old. All Smurf2-deficient mice develop visible DLBCL tumor starting at 15 months of age. Total miRNA was isolated from serum, bone marrow and spleen and were collected for all age groups for Smurf2-deficient mice and age-matched wild-type C57BL/6 mice. Using systems biology techniques, we 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. 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.
Diffuse large B-cell lymphoma (DLBCL) is the most common form of non-Hodgkin lymphoma (NHL), accounting for approximately one-third of patients diagnosed in the United States [1, 2]. Although DLBCL is curable in the majority of patients, approximately 35–40% of patients die due to disease progression, while acute and late toxicities remain an issue among treated patients [1, 2]. Detection and treatment options for DLCBL are typically developed by observational clinical studies rather than measurable biological differences [3, 4]. This has resulted in a general lack of precision medicine approaches to date in current DLBCL therapeutic paradigms [3, 5]. Varied molecular factors, however, are emerging as potential prognostic and therapeutic targets in DLBCL [2, 6]. A specific transcription factor, JUN, was shown to be frequently activated in DLBCL and highly upregulated in a large number of genes and significantly contributed to DLBCL growth through interaction with the microenvironment . Additionally, we recently showed in an analysis utilizing The Cancer Genome Atlas (TCGA) that JUN impacted older DLBCL patients . In general, continued knowledge is needed to identify specific molecular changes and potential actionable pathways for prognosis and therapeutic targets in DLBCL.
Understanding of the impact of miRNAs in cancer has greatly evolved since the first links to cancer were observed in early 2000s [50, 51]. More specifically, impact of miRNA on lymphomas was initially underestimated with only a handful of miRNAs, including miR-155 [52, 53] and a miR-16 and miR-15 combination , first thought to be the key players in B cell lymphomas. Since then, it has been discovered that a number of other miRNAs, including miR-17 [13, 19], miR-27 [19, 20, 41], miR-24 , miR-10 [19, 20], and let-7 [12, 19, 20], play an important role in lymphoma biology. This has led to many possible biomarkers and targets for cancer therapeutics typically using only a single miRNA agent for lymphoma [19, 55].