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Integrative single-cell analysis reveals human germinal center dynamics de-synchronized in B cell lymphoma

ABSTRACT: Most adult B cell lymphomas originate from germinal center (GC) B cells but it is unclear to what extent overt lymphoma B cells retain GC B cell functional dynamics or are blocked in a particular stage of the GC reaction. Here, we used integrative single-cell analysis of phenotype, gene expression and IGH sequence to track the characteristic human GC B cell program in follicular lymphoma (FL) B cells. By modeling the cyclic continuum of GC B cell transitional states, we identified characteristic patterns of synchronously expressed gene clusters. GC-specific gene expression synchrony was lost in single lymphoma B cells. Yet, distinct FL-specific cell states co-existed within single patient biopsies. Our data show that lymphoma B cells are not blocked in a GC B cell state but may adopt new dynamic modes of functional diversity, opening novel definitions of lymphoma identity.

ORGANISM(S): Homo sapiens

PROVIDER: GSE115795 | GEO | 2018/06/15

REPOSITORIES: GEO

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Project description: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. 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.

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Integrative single-cell analysis reveals human germinal center dynamics de-synchronized in B cell lymphoma

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