BioProject

Somatic mutations of the MLL2 methyltransferase gene represent a common genetic lesion in multiple cancer types. More...

Somatic mutations of the MLL2 methyltransferase gene represent a common genetic lesion in multiple cancer types. In diffuse large B cell lymphoma (DLBCL) and follicular lymphoma (FL) (collectively, over 70% of all lymphoma diagnoses), these mutations are highly recurrent and appear early during transformation, possibly in pre-malignant precursors. Here we show that FL- and DLBCL-associated MLL2 mutations impair its enzymatic activity and lead to diminished global H3K4 methylation in normal germinal-center (GC) B cells and DLBCL, consistent with the enrichment of MLL2 binding at enhancer and promoter regions marked by mono- and tri-methylation. Conditional deletion of Mll2 early during B cell development, but not after initiation of the GC reaction, leads to increased percentages and numbers of GC B cells, which feature a distinct transcriptional profile defined by the enrichment of cell-cycle regulatory and B-cell receptor signaling genes. Consistently, Mll2-deficient B cells exhibit proliferative advantage and accumulation in the S phase of the cell cycle, which is influenced by the number of cell divisions. While GC-specific loss of Mll2 was not sufficient to initiate malignant transformation, compound Mll2-deficient/BCL2-transgenic mice displayed an increased incidence of clonal lymphoproliferations resembling the features of human FL and DLBCL. These findings suggest that early MLL2 loss favors BCL2-induced lymphomagenesis by remodeling the epigenetic landscape of the cancer precursor cells. Eradication of MLL2-deficient cells may represent a rational therapeutic approach targeting early tumorigenic events. Overall design: Murine germinal center B cells (B220+CD95+PNA+) were sorted from the spleen of conditional Mll2 knock-out, Mll2 heterozygous and Mll2 wild type mice (crossed with CD19-Cre or Cg1-Cre deletor strains) and sacrificed at day 12 after immunization with sheep red blood cells (SRBC)(n=3 mice per genotype). Total RNA was extracted from single cell suspensions and processed according to the Ovation RNA Amplification System and Encore® Biotin Module protocols (both from NuGEN). Samples were analyzed on Affymetrix Mouse Genome 430 2.0 arrays. Less...