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Efficacy of BET protein proteolysis targeted chimera-based combinations against novel patient-derived models of Richter Transformation-Diffuse Large B-Cell Lymphoma [RNA-Seq]

ABSTRACT: RichterTransformation (RT) develops in CLL as an aggressive, therapy resistant diffuse large B cell lymphoma (RT-DLBCL), commonly clonally related (CLR) to the antecedent CLL. Lack of available pre-clinical models has hampered development of novel therapies for RT-DLBCL. Here,we report the profiles of genetic alterations, active enhancers, gene-expressions and anti-lymphoma drug-sensitivity patterns of first-ever established, patient-derived xenograft models of RT-DLBCLs, including CLR and clonally unrelated (CLUR) to antecedent CLL. The CLR and CLUR RT-DLBCL cells display active enhancers, higher single-cell RNA-Seq-determined mRNA, and protein-expressions of IRF4, TCF4 and BCL2. This correlated with higher sensitivity to BET inhibitor and BET-PROTAC-based combinations with ibrutinib or venetoclax, including improved in vivo tumor burden and survival in the PDX model of CLR-RT-DLBCL.

ORGANISM(S): Homo sapiens

PROVIDER: GSE154462 | GEO | 2021/08/26

REPOSITORIES: GEO

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Efficacy of BET protein proteolysis targeted chimera-based combinations against novel patient-derived models of Richter Transformation-Diffuse Large B-Cell Lymphoma [ATAC-Seq]

Project description:RichterTransformation (RT) develops in CLL as an aggressive, therapy resistant diffuse large B cell lymphoma (RT-DLBCL), commonly clonally related (CLR) to the antecedent CLL. Lack of available pre-clinical models has hampered development of novel therapies for RT-DLBCL. Here,we report the profiles of genetic alterations, active enhancers, gene-expressions and anti-lymphoma drug-sensitivity patterns of first-ever established, patient-derived xenograft models of RT-DLBCLs, including CLR and clonally unrelated (CLUR) to antecedent CLL. The CLR and CLUR RT-DLBCL cells display active enhancers, higher single-cell RNA-Seq-determined mRNA, and protein-expressions of IRF4, TCF4 and BCL2. This correlated with higher sensitivity to BET inhibitor and BET-PROTAC-based combinations with ibrutinib or venetoclax, including improved in vivo tumor burden and survival in the PDX model of CLR-RT-DLBCL.

2021-08-26 | GSE154456 | GEO

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Genomic profiling of Richter-syndrome Chronic Lymphocytic Leukemia

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

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Transcription profiling of follicular lymphoma to diffuse large cell lymphoma

Project description:Transformation of Follicular Lymphoma to Diffuse Large Cell Lymphoma: Alternative Patterns with Increased or Decreased Expression of c-myc and its Regulated genes The natural history of follicular lymphoma (FL) is frequently characterized by transformation to a more aggressive diffuse large B cell lymphoma (DLBCL). We compared the gene expression profiles between transformed DLBCL and their antecedent FL. No genes were observed to increase or decrease their expression in all the cases of histological transformation. However, two different gene expression profiles associated with the transformation process were defined, one in which c-myc and genes regulated by c-myc showed increased expression and one in which these same genes showed decreased expression. Further, there was a striking difference in gene expression profiles between transformed DLBCL and de novo DLBCL, since the gene expression profile of transformed DLBCL was more similar to their antecedent FL than to de novo DLBCL. The study demonstrates that transformation from FL to DLBCL can occur by alternative pathways and that transformed DLBCL and de novo DLBCL have very different gene expression profiles that may underlie the different clinical behaviors of these two types of morphologically similar lymphomas.

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Richter transfromation of chronic lymphocytic leukemia driven by Epstein-Barr virus reactivation during therapy-realted immunosuppression

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2005-10-18 | E-GEOD-3458 | biostudies-arrayexpress

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BRD4 inhibition sensitizes diffuse large B-cell lymphoma cells to ferroptosis

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Richter Syndrome Methylation dataset

Project description:Raw idat files for 90 RS + DLBCL + CLL samples.

| EGAD00010002194 | EGA