Genomic and transcriptomic correlates of Richter's transformation in Chronic Lymphocytic Leukemia
(2021) In Blood 137(20). p.2800-2816- Abstract
The transformation of chronic lymphocytic leukemia (CLL) to high-grade B-cell lymphoma is known as Richter's Syndrome (RS) and it is 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 clinical trial (CHOP-O) patients. 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 tumour necrosis factor receptor associated factor three (TRAF3). In the non-coding genome, we discovered AID-related and unrelated kataegis in... (More)
The transformation of chronic lymphocytic leukemia (CLL) to high-grade B-cell lymphoma is known as Richter's Syndrome (RS) and it is 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 clinical trial (CHOP-O) patients. 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 tumour necrosis factor receptor associated factor three (TRAF3). In the non-coding genome, we discovered AID-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 andTRIM13. 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 de-convolution 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 (NCT03899337).
(Less)
- author
- organization
- publishing date
- 2021-05-20
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Blood
- volume
- 137
- issue
- 20
- pages
- 17 pages
- publisher
- American Society of Hematology
- external identifiers
-
- scopus:85107087150
- pmid:33206936
- ISSN
- 1528-0020
- DOI
- 10.1182/blood.2020005650
- language
- English
- LU publication?
- yes
- id
- fb917ef9-82a4-4ca2-a8b0-2bf232ab2865
- date added to LUP
- 2020-11-26 14:42:28
- date last changed
- 2024-04-17 19:41:54
@article{fb917ef9-82a4-4ca2-a8b0-2bf232ab2865,
abstract = {{<p>The transformation of chronic lymphocytic leukemia (CLL) to high-grade B-cell lymphoma is known as Richter's Syndrome (RS) and it is 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 clinical trial (CHOP-O) patients. 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 tumour necrosis factor receptor associated factor three (TRAF3). In the non-coding genome, we discovered AID-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 andTRIM13. 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 de-convolution 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 (NCT03899337).</p>}},
author = {{Klintman, Jenny and Appleby, Niamh and Stamatopoulos, Basile and Ridout, Kate and Eyre, Toby Andrew and Robbe, Pauline and Lopez Pascua, Laura and Knight, Samantha Jl and Dreau, Helene Mp and Cabes, Maite and Popitsch, Niko and Ehinger, Mats and Martin-Subero, Iñaki and Campo, Elías and Mansson, Robert and Rossi, Davide and Taylor, Jenny C and Vavoulis, Dimitrios V and Schuh, Anna}},
issn = {{1528-0020}},
language = {{eng}},
month = {{05}},
number = {{20}},
pages = {{2800--2816}},
publisher = {{American Society of Hematology}},
series = {{Blood}},
title = {{Genomic and transcriptomic correlates of Richter's transformation in Chronic Lymphocytic Leukemia}},
url = {{http://dx.doi.org/10.1182/blood.2020005650}},
doi = {{10.1182/blood.2020005650}},
volume = {{137}},
year = {{2021}},
}