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).
Authors
- Pedro Faria Zeni (ORCID: https://orcid.org/0000-0003-0243-5983)
- Kateřina Kamarádová (ORCID: https://orcid.org/0000-0001-8128-2326)
- Václav Šeda (ORCID: https://orcid.org/0000-0003-0234-6470)
- Andrea Marečková (ORCID: https://orcid.org/0000-0001-9096-9680)
- Daniel Filip (ORCID: https://orcid.org/0000-0001-8717-5230)
- Alice Šýkorová (ORCID: https://orcid.org/0000-0002-8773-6250)
- Marek Mráz (ORCID: https://orcid.org/0000-0001-6975-8838)
- Milan Urík (ORCID: https://orcid.org/0000-0002-2872-185X)
- Nicolas Blavet (ORCID: https://orcid.org/0000-0003-2199-9119)
- Andrea Janíková (ORCID: https://orcid.org/0000-0002-2647-7769)
- Václav Hejret
- Zuzana Prouzová (ORCID: https://orcid.org/0000-0002-7507-0797)
- Katerina Musilova Litzmanova
- Miroslav Boudný (ORCID: https://orcid.org/0000-0001-5757-0424)
- Jan Oppelt (ORCID: https://orcid.org/0000-0002-3076-4840)
- Filip Kledus
- Lisa M. Rimsza (ORCID: https://orcid.org/0000-0001-8371-7207)
- Androniki Michaelou
- Heike Horn (ORCID: https://orcid.org/0000-0002-2933-005X)
- German Ott
- Jonathan W. Friedberg
- Marek Trneny
- Kvetoslava Matulova
- Alexey Danilov
- Andrew G. Evans
- Marek Borsky
- Jan Devan
- David Belada
- Sonali Sharma
- Leos Kren
- Eva Hoferkova
- Philipp Staber
- Heidi Mocikova
- Jiri Mayer
Institutions
- Central European Institute of Technology (CZ)
- University of Arizona (US)
- Charles University (CZ)
- Masaryk University (CZ)
- Robert Bosch Hospital (DE)
- Central European Institute of Technology – Masaryk University (CZ)
- University Hospital Brno (CZ)
- City of Hope (US)
- Central European Institute of Technology (AT)
- Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology (DE)
- Mayo Clinic in Arizona (US)
- University Hospital Hradec Králové (CZ)
- University Hospital Kralovske Vinohrady (CZ)
- General University Hospital in Prague (CZ)
- University of Rochester (US)
- Medical University of Vienna (AT)
- Saarland University (DE)
Publication Details
- Journal
- Leukemia
- Published
- 2026-02-19
- DOI
- https://doi.org/10.1038/s41375-026-02868-8
- Primary Topic
- Lymphoma Diagnosis and Treatment
- Type
- article
- Field-Weighted Citation Impact
- 0.00