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Title:
Clonal dynamics towards the development of venetoclax resistance in chronic lymphocytic leukemia | Nature Communications
Description:
Deciphering the evolution of cancer cells under therapeutic pressure is a crucial step to understand the mechanisms that lead to treatment resistance. To this end, we analyzed whole-exome sequencing data of eight chronic lymphocytic leukemia (CLL) patients that developed resistance upon BCL2-inhibition by venetoclax. Here, we report recurrent mutations in BTG1 (2 patients) and homozygous deletions affecting CDKN2A/B (3 patients) that developed during treatment, as well as a mutation in BRAF and a high-level focal amplification of CD274 (PD-L1) that might pinpoint molecular aberrations offering structures for further therapeutic interventions. BCL2-inhibitor venetoclax is used to treat relapsed/refractory chronic lymphocytic leukemia (CLL). Here, the authors show the clonal dynamics towards venetoclax resistance by performing whole-exome sequencing of 8 CLL patients undergoing venetoclax treatment.
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Keywords {🔍}
venetoclax, pubmed, cell, article, mutations, cells, patients, google, scholar, fig, evolution, cancer, treatment, cll, nature, cas, leukemia, data, chronic, lymphocytic, patient, cologne, samples, resistance, clonal, sequencing, cdknab, genomic, supplementary, germany, usa, central, mutation, braf, alterations, therapy, relapse, number, analysis, btg, homozygous, genome, disease, blood, university, sample, dna, deletions, methylation, copy,
Topics {✒️}
nature portfolio privacy policy roche research funding received research funding advertising research support genome-wide libraries immuno tools social media antisense bcl-2-mediated apoptosis obtained exome libraries martin peifer contributed equally oci-ly19 cell line immune-checkpoint ligand pd-l1 reprints open-label thermo fisher scientific fluorescence-activated cell sorting anti-pd-l1 antibody chronic lymphocytic leukaemia nature nature 526 nature 475 nature 524 small-cell lung cancer small-cell lung cancer chronic lymphocytic leukemia enrichment kits short-tandem repeat profiling arf induces p53-dependent avoid kit-specific biases venetoclax-sensitive cell line pmdlg/prre und pmd2 key cancer-related genes producing single-guide rna major cll-sequencing studies3 b-lymphoma cell lines ntsr2/trkb oncogenic pathway permissions integrated oncology cologne-bonn identify genome alterations clemens-martin wendtner cancer-related gene mutations national cancer institute high-level focal amplification pre-treatment sample names digital droplet pcr michael hallek & lukas related matched pre-treatment ethical review board
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headline:Clonal dynamics towards the development of venetoclax resistance in chronic lymphocytic leukemia
description:Deciphering the evolution of cancer cells under therapeutic pressure is a crucial step to understand the mechanisms that lead to treatment resistance. To this end, we analyzed whole-exome sequencing data of eight chronic lymphocytic leukemia (CLL) patients that developed resistance upon BCL2-inhibition by venetoclax. Here, we report recurrent mutations in BTG1 (2 patients) and homozygous deletions affecting CDKN2A/B (3 patients) that developed during treatment, as well as a mutation in BRAF and a high-level focal amplification of CD274 (PD-L1) that might pinpoint molecular aberrations offering structures for further therapeutic interventions. BCL2-inhibitor venetoclax is used to treat relapsed/refractory chronic lymphocytic leukemia (CLL). Here, the authors show the clonal dynamics towards venetoclax resistance by performing whole-exome sequencing of 8 CLL patients undergoing venetoclax treatment.
datePublished:2018-02-20T00:00:00Z
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Chronic lymphocytic leukaemia
Computational biology and bioinformatics
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headline:Clonal dynamics towards the development of venetoclax resistance in chronic lymphocytic leukemia
description:Deciphering the evolution of cancer cells under therapeutic pressure is a crucial step to understand the mechanisms that lead to treatment resistance. To this end, we analyzed whole-exome sequencing data of eight chronic lymphocytic leukemia (CLL) patients that developed resistance upon BCL2-inhibition by venetoclax. Here, we report recurrent mutations in BTG1 (2 patients) and homozygous deletions affecting CDKN2A/B (3 patients) that developed during treatment, as well as a mutation in BRAF and a high-level focal amplification of CD274 (PD-L1) that might pinpoint molecular aberrations offering structures for further therapeutic interventions. BCL2-inhibitor venetoclax is used to treat relapsed/refractory chronic lymphocytic leukemia (CLL). Here, the authors show the clonal dynamics towards venetoclax resistance by performing whole-exome sequencing of 8 CLL patients undergoing venetoclax treatment.
datePublished:2018-02-20T00:00:00Z
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Computational biology and bioinformatics
Science
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multidisciplinary
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name:University of Cologne
address:
name:Department of Internal Medicine I, Center of Integrated Oncology Cologne-Bonn, University of Cologne, 50937 Cologne, Germany
type:PostalAddress
type:Organization
name:University of Cologne
address:
name:Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931 Cologne, Germany
type:PostalAddress
type:Organization
name:University of Cologne
address:
name:Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany
type:PostalAddress
type:Organization
name:Viktor Achter
affiliation:
name:University of Cologne
address:
name:Computing Center, University of Cologne, 50931 Cologne, Germany
type:PostalAddress
type:Organization
name:Ulrich Lang
affiliation:
name:University of Cologne
address:
name:Computing Center, University of Cologne, 50931 Cologne, Germany
type:PostalAddress
type:Organization
name:University of Cologne
address:
name:Department of Informatics, University of Cologne, 50931 Cologne, Germany
type:PostalAddress
type:Organization
name:Barbara Eichhorst
affiliation:
name:University of Cologne
address:
name:Department of Internal Medicine I, Center of Integrated Oncology Cologne-Bonn, University of Cologne, 50937 Cologne, Germany
type:PostalAddress
type:Organization
name:Roberta Castiglione
affiliation:
name:University of Cologne
address:
name:Department of Pathology, University of Cologne, Cologne, Germany
type:PostalAddress
type:Organization
name:Stephan C. Schäfer
affiliation:
name:University of Cologne
address:
name:Department of Pathology, University of Cologne, Cologne, Germany
type:PostalAddress
type:Organization
name:Reinhard Büttner
affiliation:
name:University of Cologne
address:
name:Department of Pathology, University of Cologne, Cologne, Germany
type:PostalAddress
type:Organization
name:Karl-Anton Kreuzer
affiliation:
name:University of Cologne
address:
name:Department of Internal Medicine I, Center of Integrated Oncology Cologne-Bonn, University of Cologne, 50937 Cologne, Germany
type:PostalAddress
type:Organization
name:Hans Christian Reinhardt
affiliation:
name:University of Cologne
address:
name:Department of Internal Medicine I, Center of Integrated Oncology Cologne-Bonn, University of Cologne, 50937 Cologne, Germany
type:PostalAddress
type:Organization
name:University of Cologne
address:
name:Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931 Cologne, Germany
type:PostalAddress
type:Organization
name:University of Cologne
address:
name:Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany
type:PostalAddress
type:Organization
name:Michael Hallek
affiliation:
name:University of Cologne
address:
name:Department of Internal Medicine I, Center of Integrated Oncology Cologne-Bonn, University of Cologne, 50937 Cologne, Germany
type:PostalAddress
type:Organization
name:University of Cologne
address:
name:Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931 Cologne, Germany
type:PostalAddress
type:Organization
name:University of Cologne
address:
name:Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany
type:PostalAddress
type:Organization
name:Lukas P. Frenzel
affiliation:
name:University of Cologne
address:
name:Department of Internal Medicine I, Center of Integrated Oncology Cologne-Bonn, University of Cologne, 50937 Cologne, Germany
type:PostalAddress
type:Organization
name:University of Cologne
address:
name:Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany
type:PostalAddress
type:Organization
name:Martin Peifer
url:http://orcid.org/0000-0002-5243-5503
affiliation:
name:University of Cologne
address:
name:Department of Translational Genomics, Center of Integrated Oncology Cologne-Bonn, Medical Faculty, University of Cologne, 50931 Cologne, Germany
type:PostalAddress
type:Organization
name:University of Cologne
address:
name:Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931 Cologne, Germany
type:PostalAddress
type:Organization
email:[email protected]
PostalAddress:
name:Department of Internal Medicine I, Center of Integrated Oncology Cologne-Bonn, University of Cologne, 50937 Cologne, Germany
name:Department of Translational Genomics, Center of Integrated Oncology Cologne-Bonn, Medical Faculty, University of Cologne, 50931 Cologne, Germany
name:Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931 Cologne, Germany
name:Department of Internal Medicine I, Center of Integrated Oncology Cologne-Bonn, University of Cologne, 50937 Cologne, Germany
name:Department of Internal Medicine I, Center of Integrated Oncology Cologne-Bonn, University of Cologne, 50937 Cologne, Germany
name:Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931 Cologne, Germany
name:Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany
name:Department of Internal Medicine I, Center of Integrated Oncology Cologne-Bonn, University of Cologne, 50937 Cologne, Germany
name:Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931 Cologne, Germany
name:Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany
name:Department of Internal Medicine I, Center of Integrated Oncology Cologne-Bonn, University of Cologne, 50937 Cologne, Germany
name:Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany
name:Department of Translational Genomics, Center of Integrated Oncology Cologne-Bonn, Medical Faculty, University of Cologne, 50931 Cologne, Germany
name:Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931 Cologne, Germany
name:Department of Internal Medicine I, Center of Integrated Oncology Cologne-Bonn, University of Cologne, 50937 Cologne, Germany
name:Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931 Cologne, Germany
name:Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany
name:Laboratory of Lymphocyte Signaling and Oncoproteom, University of Cologne, 50931 Cologne, Germany
name:Department of Internal Medicine I, Center of Integrated Oncology Cologne-Bonn, University of Cologne, 50937 Cologne, Germany
name:Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931 Cologne, Germany
name:Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany
name:Laboratory of Lymphocyte Signaling and Oncoproteom, University of Cologne, 50931 Cologne, Germany
name:Department of Internal Medicine I, Center of Integrated Oncology Cologne-Bonn, University of Cologne, 50937 Cologne, Germany
name:Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany
name:Department of Internal Medicine I, Center of Integrated Oncology Cologne-Bonn, University of Cologne, 50937 Cologne, Germany
name:Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany
name:Department of Internal Medicine I, Center of Integrated Oncology Cologne-Bonn, University of Cologne, 50937 Cologne, Germany
name:Department of Internal Medicine I, Center of Integrated Oncology Cologne-Bonn, University of Cologne, 50937 Cologne, Germany
name:Department of Internal Medicine I, Center of Integrated Oncology Cologne-Bonn, University of Cologne, 50937 Cologne, Germany
name:Department of Hematology, Oncology, Immunology, Palliative Care, Infectious Diseases and Tropical Medicine, Klinikum Schwabing, 80804 Munich, Germany
name:Department of Radiology, Cologne University Hospital, 50937 Cologne, Germany
name:Department of Diagnostic and Interventional Radiology and Pediatric Radiology, Städtisches Klinikum München Schwabing, 80804 Munich, Germany
name:Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931 Cologne, Germany
name:Cologne Center for Genomics (CCG), University of Cologne, 50931 Cologne, Germany
name:Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931 Cologne, Germany
name:Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany
name:Cologne Center for Genomics (CCG), University of Cologne, 50931 Cologne, Germany
name:Department of Internal Medicine I, Center of Integrated Oncology Cologne-Bonn, University of Cologne, 50937 Cologne, Germany
name:Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931 Cologne, Germany
name:Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany
name:Computing Center, University of Cologne, 50931 Cologne, Germany
name:Computing Center, University of Cologne, 50931 Cologne, Germany
name:Department of Informatics, University of Cologne, 50931 Cologne, Germany
name:Department of Internal Medicine I, Center of Integrated Oncology Cologne-Bonn, University of Cologne, 50937 Cologne, Germany
name:Department of Pathology, University of Cologne, Cologne, Germany
name:Department of Pathology, University of Cologne, Cologne, Germany
name:Department of Pathology, University of Cologne, Cologne, Germany
name:Department of Internal Medicine I, Center of Integrated Oncology Cologne-Bonn, University of Cologne, 50937 Cologne, Germany
name:Department of Internal Medicine I, Center of Integrated Oncology Cologne-Bonn, University of Cologne, 50937 Cologne, Germany
name:Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931 Cologne, Germany
name:Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany
name:Department of Internal Medicine I, Center of Integrated Oncology Cologne-Bonn, University of Cologne, 50937 Cologne, Germany
name:Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931 Cologne, Germany
name:Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany
name:Department of Internal Medicine I, Center of Integrated Oncology Cologne-Bonn, University of Cologne, 50937 Cologne, Germany
name:Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany
name:Department of Translational Genomics, Center of Integrated Oncology Cologne-Bonn, Medical Faculty, University of Cologne, 50931 Cologne, Germany
name:Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931 Cologne, Germany
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