Our findings suggest that BCL2 gene translocations are a recurrent feature of a distinct subset of histiocytic sarcomas that are associated with follicular lymphoma; the follicular lymphoma component may be clinically occult at the time of diagnosis.
Follicular lymphoma (FL) shows co-expression of B-cell lymphoma 2 (BCL2) and CD10, whereas downexpression of CD10 is occasionally experienced in gastrointestinal (GI) FL with unknown significance.
BCL2-break-positive cases had a tendency to occur in the head and neck and showed the classical phenotype of nodal follicular lymphoma (CD10+, BCL6+, BCL2+, STMN+) compared with BCL2-break-negative PCFCLs.Del 1p36 was observed in 1 PCFCL.
This study investigates activity of the BH3 mimetic venetoclax (ABT-199), which targets BCL-2, and mechanisms of acquired resistance in FL.The sensitivity of FL cells to venetoclax treatment correlated with BCL-2/BIM ratio.
Prioritized alterations in epigenetic modulators were common and included gain-of-function EZH2 and loss-of-function ARID1A mutations (14% of diffuse large B-cell lymphomas and 22% of follicular lymphomas contained alterations in each of these two genes).
These results suggest that the molecular profile differs to some extent between FLs with and without BCL2 breaks and support the notion that FLs with and without BCL2 breaks belong to the same lymphoma entity.
Recently, point mutations of EZH2 at Tyr641 and Ala677 were identified in diffuse large B cell lymphoma and follicular lymphoma, where they drive H3K27 hypertrimethylation and cancer progression.
Analysis of the BCL2 mutation pattern in clonally related FL/FL and FL/tFL samples revealed two distinct scenarios of genomic evolution: (i) direct evolution from the antecedent FL clone, with few novel clonal mutations acquired by the tFL major clone, and (ii) evolution from a common mutated long-lived progenitor cell, which subsequently acquired distinct mutations in the FL and in the relapsed or transformed counterpart.
In a multivariate analysis, BCL2 mutations and high FL international prognostic index were independent risk factors for transformation and death due to lymphoma.
In particular, recurrent gain-of-function mutations targeting EZH2 Y641 occur most frequently in follicular lymphoma and aggressive diffuse large B-cell lymphoma and are associated with H3K27me3 hyperactivation, which contributes to lymphoma pathogenesis.
Here we performed whole-genome bisulfite, genome and transcriptome sequencing in 13 IG-MYC translocation-positive Burkitt lymphoma, nine BCL2 translocation-positive follicular lymphoma and four normal germinal center B cell samples.
Chronic B-cell receptor stimulation induces cyclic re-entries of BCL2 B cells into germinal centers that propagate clonal evolution and early follicular lymphoma progression.
Bcl-2, the founding member of a family of apoptotic regulators, was initially identified as the protein product of a gene that is translocated and overexpressed in greater than 85% of follicular lymphomas (FLs).
Here, we identify the SRY-related high-morbidity-group (HMG) box 5 (SOX5) gene on chromosome 12p12 as a novel IGH-involved translocation partner in the case of BCL2-negative follicular lymphoma (FL) with a complex karyotype including t(12;14)(p12.2;q32) by long-distance inverse PCR.
We developed a mouse model that recapitulates the FL hallmark t(14;18) translocation, which results in constitutive activation of antiapoptotic protein B cell lymphoma 2 (BCL2) in a subset of B cells, and applied a combination of molecular and immunofluorescence approaches to track normal and t(14;18)(+) memory B cells in human and BCL2-overexpressing B cells in murine lymphoid tissues.