Follicular Lymphoma (FL)

Overview

Follicular lymphoma (FL) is an indolent B-cell non-Hodgkin lymphoma (NHL) of germinal-center B-cell origin. It sits at OncoTree level 5 under the MBN (Mature B-Cell Neoplasms) lineage. The t(14;18) BCL2/IGH translocation is a hallmark, but somatic mutations in histone-modifying genes — particularly KMT2D — are now recognized as equally prevalent founding events.

Cohorts in the corpus

  • 35 FL tumors analyzed as part of a 127-sample B-cell NHL cohort (plus 10 DLBCL cell lines); 14 cases with matched tumor/normal whole-genome or whole-exome sequencing; validation of KMT2D in 35 FL and 37 DLBCL via Illumina amplicon resequencing; validation of MEF2B in 261 FL cases via Sanger sequencing; dataset nhl_bcgsc_2011. PMID:21796119

Recurrent alterations

  • KMT2D (MLL2): mutated in 89% (31/35) of FL; 91% of mutations inactivating (frameshift indels, nonsense, splice-site); bi-allelic inactivation confirmed in 8 FL cases; as prevalent as t(14;18), suggesting a foundational role in FL pathogenesis. PMID:21796119
  • MEF2B: recurrent non-synonymous mutations in 15.3% of FL; 59.4% of variants cluster at four residues (K4, Y69, N81, D83); restricted to GCB subtype; cooperates with CREBBP/EP300 in histone acetylation. PMID:21796119
  • EZH2: Y641 gain-of-function hotspot with allelic imbalance favouring the mutant allele; GCB-enriched; enhances H3K27 trimethylation. PMID:21796119
  • CREBBP: inactivating mutations (nonsense, missense); HAT activity disruption. PMID:21796119
  • BCL2: missense mutations via somatic hypermutation; allelic imbalance favouring the translocated allele. PMID:21796119
  • TNFRSF14: nonsense mutations; tumor suppressor; GCB-restricted. PMID:21796119

Subtypes

  • GCB subtype dominates FL; characterized by KMT2D, MEF2B, EZH2, and TNFRSF14 mutations; distinct from ABC-enriched mutational profile seen in DLBCL. PMID:21796119

Therapeutic landscape

  • KMT2D inactivation (89%) and EZH2 gain-of-function mutations implicate disrupted histone methylation as a therapeutic target; EZH2 inhibitors (e.g., tazemetostat) have clinical relevance in EZH2-mutant FL. PMID:21796119

Sources

  • PMID:21796119 — Morin et al. (2011), frequent mutation of histone-modifying genes in non-Hodgkin lymphoma (DLBCL and FL).

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