Abstract
Simple SummaryAround 30–40% of patients with diffuse large B cell lymphoma suffer early relapse after standard chemotherapy, but today no prediction whether a patient belongs to this group is possible. MicroRNA are small nucleotide sequences that regulate cellular functions via post-transcriptional modification of gene expression and can serve as prognostic biomarkers. A novel two-step strategy first used a small patient discovery group to identify possible microRNA candidates by comparing their levels in chemosensitive and chemoresistant patients via microarray. Overexpression of these microRNA was then analyzed in a large patient cohort and, as a result, three new microRNA biomarkers with prognostic potential could be identified. Early identification of those patients being at risk of failure with standard therapy is a prerequisite to develop more efficient treatments and a step towards precision medicine.Diffuse large B cell lymphoma (DLBCL) treatment with R-CHOP regimen produces 5-year progression-free survival and overall survival of around 60–70%. Our objective was to discover prognostic biomarkers allowing early detection of the remaining 30–40% with poor long-term outcome. For this purpose, we applied a novel strategy: from a cohort of DLBCL patients, treated with standard therapy, a discovery group of 12 patients with poor prognosis (advanced stage III–IV, R-IPI > 2) was formed, consisting of six chemoresistant (refractory/early relapse < 12 months) and six chemosensitive (complete remission > 3 years) subjects. By using microarray assays, the most differentially expressed miRNAs were defined as an initial set of prognostic miRNA candidates. Their expression was then analyzed in a validation cohort of 68 patients and the three miRNAs with the most significant impact on event-free and overall survival were selected. In the DLBCL cell line U-2932 the transfection with miR-1244 and miR-193b-5p, but not miR-1231, blocked the effect of CHOP on cell viability. A subsequent gene set enrichment analysis in patients revealed the implication of the first two miRNAs in cell cycle control and chemoresistance-related pathways, whereas the last one was involved in immunological processes. In conclusion, this novel strategy identified three promising prognostic markers for DLBCL patients at high risk of failure with standard therapy.
Highlights
Diffuse large B cell lymphoma (DLBCL) is the most common subtype of lymphoid neoplasm characterized as a heterogeneous group of aggressive lymphomas
With or without radiotherapy were retrospectively selected from three Spanish Centers (Son Espases University Hospital (HUSE), n = 113; Son Llàtzer Hospital (HSLL), n = 25; and Hospital del Mar (HM), n = 18)
An important issue was that miRNAs can be used as biomarkers for diagnosis, classification, prognosis, or treatment outcome, which leads to different sets of biomarkers and a limited number of available studies in each category
Summary
Diffuse large B cell lymphoma (DLBCL) is the most common subtype of lymphoid neoplasm characterized as a heterogeneous group of aggressive lymphomas. Treatment of DLBCL is relatively homogeneous and standard, mainly based on the R-CHOP regimen that produces complete remission (CR) rates of around 70–90% [1,2], and 5-year progressionfree survival (PFS) and overall survival (OS) of around 60–70% [3] Still, this means that the standard therapy fails for 30–40% of patients in the long term, so new approaches with better treatment outcomes, for example, the use of novel drugs or other bioactive compounds, are still needed. Other studies selected miRNAs with prognostic value on DLBCL based on differential expression of miRNAs regarding OS, cell origin, non-tumoral lymphoid tissue, the comparison of different histologies or miRNAs identified in other malignancies [14–21] None of those experimental designs were directly focused on resistance to chemotherapy. Our goal was to analyze which miRNAs might be associated with chemosensitivity or chemoresistance to first line treatment in DLBCL patients, including their correlation with standard prognostic factors at diagnosis and their role in survival as well as to corroborate their biological activity in vitro in a DLBCL cell line
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