Deregulation of ETS1 and FLI1 contributes to the pathogenesis of diffuse large B-cell lymphoma

Abstract

Key Points• A recurrent gain of a region of chromosome 11 (11q24.3) occurs in up to one-quarter of cases of diffuse large B-cell lymphoma.• ETS1 and FLI1 genes are overexpressed and determine proliferation, survival, and differentiation arrest of the lymphoma cells.Diffuse large B-cell lymphoma (DLBCL) is the most common form of human lymphoma. DLBCL is a heterogeneous disease characterized by different genetic lesions. We herein report the functional characterization of a recurrent gain mapping on chromosome 11q24.3, found in 23% of 166 DLBCL cases analyzed. The transcription factors ETS1 and FLI1, located within the 11q24.3 region, had significantly higher expression in clinical samples carrying the gain. Functional studies on cell lines showed that ETS1 and FLI1 cooperate in sustaining DLBCL proliferation and viability and regulate genes involved in germinal center differentiation. Taken together, these data identify the 11q24.3 gain as a recurrent lesion in DLBCL leading to ETS1 and FLI1 deregulated expression, which can contribute to the pathogenesis of this disease. (Blood. 2013;122(13):2233-2241) IntroductionDiffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma, accounting for 25% to 30% of adult cases in western countries, and it is characterized by heterogeneous histopathological, biological, and clinical features.1 DLBCL has been molecularly classified in at least 3 subtypes, reflecting different stages of B-cell differentiation: germinal center B-cell-like DLBCL (GCB) from germinal center (GC) centroblasts, activated B-cell-like DLBCL (ABC) from GC cells undergoing plasmacytic differentiation, and an intermediate type 3 DLBCL. 2 Physiological GC B-cell differentiation requires a complex transcriptional program and DLBCL displays recurrent genetic abnormalities that typically circumvent this normal genetic program, allowing the neoplastic B cells to avoid plasmacytic differentiation and evade apoptosis.2 Briefly, chromosomal translocations involving the BCL2 oncogene and mutations of the EZH2 methyltransferase are almost exclusively observed in GCB DLBCL, 3 whereas ABC DLBCL are preferentially associated with a disruption of terminal B-cell differentiation program (ie, PRDM1 inactivation and BCL6 deregulation) 4,5 and constitutive activation of the nuclear factor kB (NF-kB) transcription pathway (most commonly via somatic mutations of TNFAIP3, CARD11, CD79B, and MYD88). [6][7][8] Other recurrent lesions can be found in all the DLBCL subtypes, including inactivation of histone and/or chromatin modifying genes CREBBP, EP300, and MLL2 9,10 and of genes involved in immune recognition, such as b2-microglobulin and CD58. 11 It is likely that additional, undescribed genetic defects may also contribute to the pathogenesis of DLBCL.In the present study, aimed to identify new recurrent genetic defects in DLBCL, we performed genomic profiling analysis on 166 DLBCL samples, which enabled us to characterize a new recurrent lesion on chromosome 11q24.3 occurring in up to onequarter of...

A recurrent 11q aberration pattern characterizes a subset of MYC-negative high-grade B-cell lymphomas resembling Burkitt lymphoma

“…Alterations of the 11q chromosomal region are not frequent in typical BL 31,32 but gains/amplifications of 11q22-q24 are found in approximately 8% to 15% of DLBCL 33,34 and also in GC-derived IRF4-translocation-positive lymphomas. 35 Nevertheless, the region of gain in these cases (minimal region at 11q23.2-q23.3) is not coincident with the minimal region observed in the present series.…”

“…Additional structures or biophysical studies of ETS1 would be required to resolve the possible roles of these positions in protein function. High levels of expression associated with gains of the 11q24.3 (including FLI1 and ETS1) have been also seen in these genes in DLBCL patients, 34 although a different mechanism seems to be involved in these cases.…”

PRDM1/BLIMP1 is commonly inactivated in anaplastic large T-cell lymphoma

“…23 Data were first extracted with the Illumina GenomeStudio software and then imported in GenomicsSuite 6.4 (Partek) and quantile normalized. Differentially expressed transcripts were identified by analysis of variance (ANOVA) (fold change, .1.5; false discovery rate, ,0.2).…”

Chemical stresses fail to mimic the unfolded protein response resulting from luminal load with unfolded polypeptides

“…Gene expression profile analysis was performed using Illumina HumanHT-12 v4 Expression BeadChip, as previously described (65).The data were analyzed with Genomic Suite (Partek). Statistical significance was assessed by t-tests (p<0.05) and fold change greater than 1.2 or smaller than 0.8.…”