Early seeding of future Richter transformation in chronic lymphocytic leukemia
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PROVIDER: EGAS00001006327 | EGA |
REPOSITORIES: EGA
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Project description:Richter syndrome (RS) occurs in up to 15% of patients with chronic lymphocytic leukemia (CLL). While RS, usually represented by the histologic transformation to a diffuse large B-cell lymphoma (DLBCL), is associated with a very poor outcome, especially when clonally related to the pre-existing CLL, mechanisms leading to RS have not been clarified yet. To better understand the pathogenesis of RS, we analyzed a series of cases including: 59 RS, 28 CLL-phase of RS, 315 CLL and 127 de novo DLBCL. RS demonstrated a genomic complexity intermediate between CLL and DLBCL. Cell cycle deregulation via inactivation of TP53 and of CDKN2A was a main mechanism in the histologic transformation from CLL-phase, being present in approximately half of the cases, and affected the outcome of the RS patients. A second major subgroup was characterized by the presence of trisomy 12 and comprised one third of the cases. While RS shared some of the lesions seen in de novo DLBCL, its genomic profile was clearly separate. The CLL-phase preceding RS had not a generalized increase in genomic complexity when compared with untransformed CLL, but it presented clear differences in the frequency of specific genetic lesions. Genomic profiling of Richter-syndrome Chronic Lymphocytic Leukemia
2013-09-20 | E-GEOD-50252 | biostudies-arrayexpress
Project description:Richter syndrome (RS) occurs in up to 15% of patients with chronic lymphocytic leukemia (CLL). While RS, usually represented by the histologic transformation to a diffuse large B-cell lymphoma (DLBCL), is associated with a very poor outcome, especially when clonally related to the pre-existing CLL, mechanisms leading to RS have not been clarified yet. To better understand the pathogenesis of RS, we analyzed a series of cases including: 59 RS, 28 CLL-phase of RS, 315 CLL and 127 de novo DLBCL. RS demonstrated a genomic complexity intermediate between CLL and DLBCL. Cell cycle deregulation via inactivation of TP53 and of CDKN2A was a main mechanism in the histologic transformation from CLL-phase, being present in approximately half of the cases, and affected the outcome of the RS patients. A second major subgroup was characterized by the presence of trisomy 12 and comprised one third of the cases. While RS shared some of the lesions seen in de novo DLBCL, its genomic profile was clearly separate. The CLL-phase preceding RS had not a generalized increase in genomic complexity when compared with untransformed CLL, but it presented clear differences in the frequency of specific genetic lesions.
2013-09-20 | GSE50252 | GEO
Project description:Richter syndrome (RS) derives from the rare transformation of chronic lymphocytic leukemia (CLL) into an aggressive lymphoma, most commonly of the diffuse large B cell lymphoma (DLBCL) type. The molecular pathogenesis of RS is only partially understood. By combining whole-exome sequencing and copy-number analysis of 9 CLL-RS pairs and of an extended panel of 43 RS cases, we show that this aggressive disease typically arises from the predominant CLL clone by acquiring an average of ?20 genetic lesions/case. RS lesions are heterogeneous in terms of load and spectrum among patients, and include those involved in CLL progression and chemorefractoriness (TP53 disruption and NOTCH1 activation) as well as some not previously implicated in CLL or RS pathogenesis. In particular, disruption of the CDKN2A/B cell cycle regulator is associated with ?30% of RS cases. Finally, we report that the genomic landscape of RS is significantly different from that of de novo DLBCL, suggesting that they represent distinct disease entities. These results provide insights into RS pathogenesis, and identify dysregulated pathways of potential diagnostic and therapeutic relevance.
| S-EPMC3804949 | biostudies-literature
Project description:The transformation of chronic lymphocytic leukemia (CLL) to high-grade B-cell lymphoma is known as Richter syndrome (RS), a rare event with dismal prognosis. In this study, we conducted whole-genome sequencing (WGS) of paired circulating CLL (PB-CLL) and RS biopsies (tissue-RS) from 17 patients recruited into a clinical trial (CHOP-O). We found that tissue-RS was enriched for mutations in poor-risk CLL drivers and genes in the DNA damage response (DDR) pathway. In addition, we identified genomic aberrations not previously implicated in RS, including the protein tyrosine phosphatase receptor (PTPRD) and tumor necrosis factor receptor-associated factor 3 (TRAF3). In the noncoding genome, we discovered activation-induced cytidine deaminase-related and unrelated kataegis in tissue-RS affecting regulatory regions of key immune-regulatory genes. These include BTG2, CXCR4, NFATC1, PAX5, NOTCH-1, SLC44A5, FCRL3, SELL, TNIP2, and TRIM13. Furthermore, differences between the global mutation signatures of pairs of PB-CLL and tissue-RS samples implicate DDR as the dominant mechanism driving transformation. Pathway-based clonal deconvolution analysis showed that genes in the MAPK and DDR pathways demonstrate high clonal-expansion probability. Direct comparison of nodal-CLL and tissue-RS pairs from an independent cohort confirmed differential expression of the same pathways by RNA expression profiling. Our integrated analysis of WGS and RNA expression data significantly extends previous targeted approaches, which were limited by the lack of germline samples, and it facilitates the identification of novel genomic correlates implicated in RS transformation, which could be targeted therapeutically. Our results inform the future selection of investigative agents for a UK clinical platform study. This trial was registered at www.clinicaltrials.gov as #NCT03899337.
| S-EPMC8163497 | biostudies-literature
Project description:Richter transformation (RT) is a paradigmatic evolution of chronic lymphocytic leukemia (CLL) into a very aggressive large B cell lymphoma conferring a dismal prognosis. The mechanisms driving RT remain largely unknown. We characterized the whole genome, epigenome and transcriptome, combined with single-cell DNA/RNA-sequencing analyses and functional experiments, of 19 cases of CLL developing RT. Studying 54 longitudinal samples covering up to 19 years of disease course, we uncovered minute subclones carrying genomic, immunogenetic and transcriptomic features of RT cells already at CLL diagnosis, which were dormant for up to 19 years before transformation. We also identified new driver alterations, discovered a new mutational signature (SBS-RT), recognized an oxidative phosphorylation (OXPHOS)high-B cell receptor (BCR)low-signaling transcriptional axis in RT and showed that OXPHOS inhibition reduces the proliferation of RT cells. These findings demonstrate the early seeding of subclones driving advanced stages of cancer evolution and uncover potential therapeutic targets for RT.
| S-EPMC9388377 | biostudies-literature
Project description:The Wnt-signalling pathway is one of the core de-regulated pathways in chronic lymphocytic leukemia (CLL), activated in a subset of patients by somatic coding mutations. Here we describe an alternative mechanism of Wnt-activation in malignant B cells, mediated by Notch2 activity in mesenchymal stromal cells (MSC) in the tumor microenvironment. We identified that tumor cells specifically induce and activate Notch2 in MSCs. Notch2 orchestrates the expression of target genes essential for the activation of canonical Wnt-signaling in CLL cells. Mechanistically, stromal Notch2 mediates the stabilization of â-catenin by inhibiting the activation of Gsk3-â in malignant B cells. Pharmacological inhibition of the Wnt-pathway mitigates microenvironment-mediated survival of malignant B cells in vitro. Similarly, inhibition of Notch-signaling impaired survival of CLL cells and disease engraftment in a PDX mouse model. Notch2 activation in the tumour microenvironment is a pre-requisite for the GSK3-â dependent activation of the canonical Wnt-signaling in tumor cells.
2018-09-19 | PXD010401 | Pride
Project description:Richter transformation (RT) is a poorly understood complication of chronic lymphocytic leukemia (CLL) with a dismal prognosis. It is associated with a switch in histopathology and biology, generally with a transformation of the original CLL clone to diffuse large B-cell lymphoma (DLBCL) or less frequently to Hodgkin's variant of Richter transformation (HVRT). It occurs in 2-10% of CLL patients, with an incidence rate of 0.5-1% per year, and may develop in treatment-naïve patients, although it is more common following therapy. In recent years, there has been a deeper understanding of the molecular pathogenesis of RT that involves the inactivation of the TP53 tumor suppressor gene in 50-60% of cases and the activation of aberrations of NOTCH1 and MYC pathways in about 30% of cases. Compared to the preceding CLL, 80% of cases with DLBCL-RT and 30% of HVRT harbor the same IGHV-D-J rearrangements, indicating a clonal evolution of the disease, while the remaining cases represent de novo lymphomas that are clonally unrelated. Despite advances in understanding the molecular variations and the pathogenesis of the disease, there is still no significant improvement in patient outcomes. However, if no clinical trials were designed for patients with RT in the past, now there many studies for these patients that incorporate new drugs and novel combinations that are being explored. In this review, we summarize the new information accumulated on RT with special emphasis on results involving the novel therapy tested for this entity, which represents an unmet clinical need.
| S-EPMC8533993 | biostudies-literature
Project description: Not available
| S-EPMC7509865 | biostudies-literature
Project description:Ibrutinib is a highly effective targeted therapy for chronic lymphocytic leukemia (CLL). However, ibrutinib must be discontinued in a subset of patients due to progressive CLL or transformation to aggressive lymphoma (Richter transformation). Transformation occurs early in the course of therapy and has an extremely poor prognosis. Thus, identification of prognostic markers associated with transformation is of utmost importance. Near-tetraploidy (4 copies of most chromosomes within a cell) has been reported in various lymphomas, but its incidence and significance in CLL has not been described. Using fluorescence in situ hybridization, we detected near-tetraploidy in 9 of 297 patients with CLL prior to beginning ibrutinib treatment on 1 of 4 clinical trials (3.0%; 95% confidence interval [CI], 1.4%-5.7%). Near-tetraploidy was associated with aggressive disease characteristics: Rai stage 3/4 (P = .03), deletion 17p (P = .03), and complex karyotype (P = .01). Near-tetraploidy was also associated with ibrutinib discontinuation due to Richter transformation (P < .0001), but not due to progressive CLL (P = .41). Of the 9 patients with near-tetraploidy, 6 had Richter transformation with diffuse large B-cell lymphoma. In a multivariable model, near-tetraploidy (hazard ratio [HR], 8.66; 95% CI, 3.83-19.59; P < .0001) and complex karyotype (HR, 4.77; 95% CI, 1.42-15.94; P = .01) were independent risk factors for discontinuing ibrutinib due to transformation. Our results suggest that near-tetraploidy is a potential prognostic marker for Richter transformation to assess in patients going on ibrutinib.
| S-EPMC5728464 | biostudies-literature
Project description:Richter syndrome (RS) is the aggressive transformation of Chronic Lymphocytic Leukemia, mostly with Diffuse Large B-Cell Lymphoma histology. While histologically similar, RS and de novo DLBCLs present with different clinical courses. We characterized the RS epigenome by combining genome-wide DNA methylation with transcriptome-sequencing on a large RS cohort.
| EGAS00001005495 | EGA