Multi-omics of Richter syndrome
Ontology highlight
ABSTRACT:
PROVIDER: EGAS00001005495 | EGA |
REPOSITORIES: EGA
Similar Datasets
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:Unlike many other hematologic malignancies, Richter syndrome (RS), an aggressive B cell lymphoma originating from indolent chronic lymphocytic leukemia, is responsive to PD-1 blockade. To discover the determinants of response, we analyzed single-cell transcriptome data generated from 17 bone marrow samples longitudinally collected from 6 RS patients. Response was associated with intermediate exhausted CD8 effector/effector memory T cells marked by high expression of the transcription factor ZNF683, determined to be evolving from stem-like memory cells and divergent from terminally exhausted cells. This signature overlapped with that of tumor-infiltrating populations from PD-1 responsive solid tumors. ZNF683 was found to directly target key T cell genes (TCF7, LMO2, CD69) and impact pathways of T cell cytotoxicity and activation. Analysis of pre-treatment peripheral blood from 10 independent RS PD-1 treated patients, as well as solid tumor PD-1 treated patients, supported an association of ZNF683high T cells with response.
2023-09-11 | GSE241090 | GEO
Project description:Unlike many other hematologic malignancies, Richter syndrome (RS), an aggressive B cell lymphoma originating from indolent chronic lymphocytic leukemia, is responsive to PD-1 blockade. To discover the determinants of response, we analyzed single-cell transcriptome data generated from 17 bone marrow samples longitudinally collected from 6 RS patients. Response was associated with intermediate exhausted CD8 effector/effector memory T cells marked by high expression of the transcription factor ZNF683, determined to be evolving from stem-like memory cells and divergent from terminally exhausted cells. This signature overlapped with that of tumor-infiltrating populations from PD-1 responsive solid tumors. ZNF683 was found to directly target key T cell genes (TCF7, LMO2, CD69) and impact pathways of T cell cytotoxicity and activation. Analysis of pre-treatment peripheral blood from 10 independent RS PD-1 treated patients, as well as solid tumor PD-1 treated patients, supported an association of ZNF683high T cells with response.
2023-09-11 | GSE241009 | GEO
Project description:Unlike many other hematologic malignancies, Richter syndrome (RS), an aggressive B cell lymphoma originating from indolent chronic lymphocytic leukemia, is responsive to PD-1 blockade. To discover the determinants of response, we analyzed single-cell transcriptome data generated from 17 bone marrow samples longitudinally collected from 6 RS patients. Response was associated with intermediate exhausted CD8 effector/effector memory T cells marked by high expression of the transcription factor ZNF683, determined to be evolving from stem-like memory cells and divergent from terminally exhausted cells. This signature overlapped with that of tumor-infiltrating populations from PD-1 responsive solid tumors. ZNF683 was found to directly target key T cell genes (TCF7, LMO2, CD69) and impact pathways of T cell cytotoxicity and activation. Analysis of pre-treatment peripheral blood from 10 independent RS PD-1 treated patients, as well as solid tumor PD-1 treated patients, supported an association of ZNF683high T cells with response. CUT&RUN sequencing for histone modifications H3K4me3, IgG isotype (control) and ZNF683 (Hobit) on/off
2023-09-11 | GSE241010 | GEO
Project description:Richter’s syndrome (RS) is an aggressive B-cell lymphoma arising from chronic lymphocytic leukemia (CLL). RS patients are generally unresponsive both to conventional and B-cell receptor-targeted agents such as ibrutinib. Mouse models that mimic the biology and therapeutic response of RS are lacking, which hampers the development of alternative treatment strategies urgently needed to improve the dismal outcome of RS patients. Aberrant Myc expression is a major factor of RS pathogenesis. To investigate Myc overexpression in the context of CLL, we generated Eµ-TCL1 mice with B-cell restricted Myc expression. Eµ-TCL1xMyc mice uniformly developed highly aggressive lymphoid disease with histologically and immunophenotypically distinct concomitant CLL and B-cell lymphoma, leading to a significantly reduced lifespan. Injection of cells from diseased Eμ-TCL1xMyc into WT mice established a disease similar to that in double-transgenic mice. Both Eμ-TCL1xMyc mice and mice with disease after adoptive transfer failed to respond to ibrutinib. Effective and durable disease control was however observed by selective inhibition of nuclear export protein exportin-1 (XPO1) using a compound currently in clinical development for relapsed/refractory malignancies, including CLL and lymphoma. Altogether, the Eµ-TCL1xMyc mouse model represents a new preclinical tool for experimental drug testing of aggressive lymphoma in the context of CLL, mimicking clinical behavior and therapeutic responses seen in RS patients.
2019-07-11 | GSE129515 | GEO
Project description:Raw idat files for 90 RS + DLBCL + CLL samples.
| EGAD00010002194 | EGA
Project description:<p><b>Analysis of the chronic lymphocytic leukemia coding genome: role of NOTCH1 mutational activation</b></p> <p>The pathogenesis of chronic lymphocytic leukemia (CLL), the most common leukemia in adults, is still largely unknown since the full spectrum of genetic lesions that are present in the CLL genome, and therefore the number and identity of dysregulated cellular pathways, have not been identified. By combining next-generation sequencing and copy number analysis, we show here that the typical CLL coding genome contains less than 20 clonally represented gene alterations/case, including predominantly non-silent mutations and fewer copy number aberrations. These analyses led to the discovery of several genes not previously known to be altered in CLL. While most of these genes were affected at low frequency in an expanded CLL screening cohort, mutational activation of NOTCH1, observed in 8.3% of CLL at diagnosis, was detected at significantly higher frequency during disease progression toward Richter transformation (31.0%) as well as in chemorefractory CLL (20.8%). Consistent with the association of NOTCH1 mutations with clinically aggressive forms of the disease, NOTCH1 activation at CLL diagnosis emerged as an independent predictor of poor survival. These results provide initial data on the complexity of the CLL coding genome and identify a dysregulated pathway of diagnostic and therapeutic relevance.</p> <p><b>Genetic Lesions associated with Chronic Lymphocytic Leukemia transformation to Richter Syndrome</b></p> <p>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 type (DLBCL). 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 locus 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.</p>
| phs000364 | dbGaP
Project description:Purpose: Richter’s Transformation (RT) is a poorly understood and often fatal progression of chronic lymphocytic leukemia (CLL) manifesting histologically as diffuse large B-cell lymphoma. PRMT5 is implicated in lymphomagenesis, but its role in CLL or RT progression is unknown. We demonstrate herein that tumors uniformly overexpress PRMT5 in patients with progression to RT. Furthermore, mice with B-specific overexpression of hPRMT5 developed a B-lymphoid expansion with increased risk of death, and Eµ-PRMT5/TCL1 double transgenic mice uniformly developed a highly aggressive disease that histologically resembles RT; where large-scale transcriptional profiling identified unique oncogenic pathways that mediate PRMT5-driven disease progression. Taken together, the discovery that PRMT5 drives oncogenic pathways promoting RT provides a compelling rationale for clinical investigation of PRMT5 inhibitors such as PRT382 in aggressive CLL/RT cases
2022-12-07 | GSE183426 | GEO
Project description:Purpose: Richter’s Transformation (RT) is a poorly understood and often fatal progression of chronic lymphocytic leukemia (CLL) manifesting histologically as diffuse large B-cell lymphoma. PRMT5 is implicated in lymphomagenesis, but its role in CLL or RT progression is unknown. We demonstrate herein that tumors uniformly overexpress PRMT5 in patients with progression to RT. Furthermore, mice with B-specific overexpression of hPRMT5 developed a B-lymphoid expansion with increased risk of death, and Eµ-PRMT5/TCL1 double transgenic mice uniformly developed a highly aggressive disease that histologically resembles RT; where large-scale transcriptional profiling identified unique oncogenic pathways that mediate PRMT5-driven disease progression. Taken together, the discovery that PRMT5 drives oncogenic pathways promoting RT provides a compelling rationale for clinical investigation of PRMT5 inhibitors such as PRT382 in aggressive CLL/RT cases
2022-12-07 | GSE183425 | GEO