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<p>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 (<i>n</i> = 11 pairs). This revealed differential expression of 1,075 mRNAs and 19 miRNAs, including repression of <i>miR-29</i> family in tFL (<i>miR-29a/b/c</i>). Further analysis uncovered that MYC directly transcriptionally represses <i>miR-29</i> 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&#xa0;tFL and&#xa0;contrasted with the reduced T-cell numbers in tFL niches. Thus, the MYC-<i>miR-29</i>-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 <i>miR-29s(a/b/c)</i> were associated with shorter overall survival (OS) and progression-free survival in FL (<i>n</i> = 185), including in a multivariate analysis. Low <i>miR-29c</i> was also associated with shorter OS in a validation cohort (<i>n</i> = 92) from the first-line R-CHOP therapy clinical trial (SWOG S0016, NCT00006721).</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月19日

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  • Daniel Filip,
  • Katerina Litzmanova,
  • Androniki Michaelou,
  • Filip Kledus,
  • Jan Devan,
  • Miroslav Boudny,
  • Eva Hoferkova,
  • Sonali Sharma,
  • Vaclav Seda,
  • Pedro Faria Zeni,
  • Marek Borsky,
  • Kvetoslava Matulova,
  • Leos Kren,
  • Jan Oppelt,
  • Nicolas Blavet,
  • Vaclav Hejret,
  • Milan Urik,
  • Andrea Mareckova,
  • Lisa M. Rimsza,
  • Katerina Kamaradova,
  • David Belada,
  • Alice Sykorova,
  • Heidi Mocikova,
  • Marek Trneny,
  • Zuzana Prouzova,
  • Andrew G. Evans,
  • Alexey Danilov,
  • Heike Horn,
  • German Ott,
  • Philipp Staber,
  • Jiri Mayer,
  • Jonathan W. Friedberg,
  • Andrea Janikova,
  • Marek Mraz

摘要

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).