Repression of miR-29 via MYC leads to increased CD40 signaling in transformed follicular lymphoma

Follicular lymphoma (FL) patients are at risk of disease transformation to aggressive high-grade lymphoma (tFL). While several genetic alterations have been implicated in tFL, the role of microenvironmental interactions and post-transcriptional regulation by non-coding RNAs remains poorly understood. We performed the first matched profiling of mRNAs and short non-coding RNAs (miRNAs) in paired FL and tFL samples (n = 11 pairs). This revealed differential expression of 1,075 mRNAs and 19 miRNAs, including repression of miR-29 family in tFL (miR-29a/b/c). Further analysis uncovered that MYC directly transcriptionally represses miR-29 in tFL, resulting in the upregulation of its target TRAF4. TRAF4 upregulation contributes to CD40 signaling being strongly activated in tFL and supports malignant B-cell proliferation. Notably, this increased CD40 pathway activity in 90% of tFL and contrasted with the reduced T-cell numbers in tFL niches. Thus, the MYC-miR-29-TRAF4 axis and increased CD40 signaling propensity may serve as tFL cells’ adaptation to reduced numbers of CD40L+ T-cells. Moreover, lower levels of all miR-29s(a/b/c) were associated with shorter overall survival (OS) and progression-free survival in FL (n = 185), including in a multivariate analysis. Low miR-29c was also associated with shorter OS in a validation cohort (n = 92) from the first-line R-CHOP therapy clinical trial (SWOG S0016, NCT00006721).