Page 219 - Haematologica May 2020

Chronic Lymphocytic Leukemia
Genomic alterations in high-risk chronic lymphocytic leukemia frequently affect cell cycle key regulators and NOTCH1-regulated transcription
Ferrata Storti Foundation
Haematologica 2020 Volume 105(5):1379-1390
Jennifer Edelmann,1,2 Karlheinz Holzmann,3 Eugen Tausch,1 Emily A. Saunderson,2 Billy M. C. Jebaraj,1 Daniela Steinbrecher,1 Anna Dolnik,1 Tamara J. Blätte,1 Dan A. Landau,4,5 Jenny Saub,1 Sven Estenfelder,1 Stefan Ibach,6 Florence Cymbalista,7 Veronique Leblond,8 Alain Delmer,9 Jasmin Bahlo,10 Sandra Robrecht,10 Kirsten Fischer,10 Valentin Goede,10 Lars Bullinger,1,11 Catherine J. Wu,4 Daniel Mertens,1, Gabriella Ficz,2 John G. Gribben,2 Michael Hallek,10 Hartmut Dӧhner1 and Stephan Stilgenbauer1
1Department of Internal Medicine III, Ulm University, Ulm, Germany; 2Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK; 3Genomics Core Facility, Ulm University, Ulm, Germany; 4Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA, USA; 5New York Genome Center, New York, NY, USA; 6Wissenschaftlicher Service Pharma GmbH (WiSP), Langenfeld, Germany; 7Service d’Hématologie Biologique, Hôpital Avicenne, Bobigny, France; 8Service d’Hématologie, Hôpital Pitié-Salpêtrière, Paris, France; 9Service d’Hématologie Clinique, CHU de Reims, Reims, France; 10Department of Internal Medicine I, University of Cologne, Cologne, Germany and 11Department of Hematology, Oncology and Tumor Immunology, Charité University Medicine Berlin, Campus Virchow Klinikum, Berlin, Germany
ABSTRACT
To identify genomic alterations contributing to the pathogenesis of high-risk chronic lymphocytic leukemia (CLL) beyond the well- established role of TP53 aberrations, we comprehensively ana- lyzed 75 relapsed/refractory and 71 treatment-naïve high-risk cases from prospective clinical trials by single nucleotide polymorphism arrays and targeted next-generation sequencing. Increased genomic complexity was a hallmark of relapsed/refractory and treatment-naïve high-risk CLL. In relapsed/refractory cases previously exposed to the selective pressure of chemo(immuno)therapy, gain(8)(q24.21) and del(9)(p21.3) were particu- larly enriched. Both alterations affect key regulators of cell-cycle progres- sion, namely MYC and CDKN2A/B. While homozygous CDKN2A/B loss has been directly associated with Richter transformation, we did not find this association for heterozygous loss of CDKN2A/B. Gains in 8q24.21 were either focal gains in a MYC enhancer region or large gains affecting the MYC locus, but only the latter type was highly enriched in relapsed/refractory CLL (17%). In addition to a high frequency of NOTCH1 mutations (23%), we found recurrent genetic alterations in SPEN (4% mutated), RBPJ (8% deleted) and SNW1 (8% deleted), all affecting a protein complex that represses transcription of NOTCH1 tar- get genes. We investigated the functional impact of these alterations on HES1, DTX1 and MYC gene transcription and found derepression of these NOTCH1 target genes particularly with SPEN mutations. In sum- mary, we provide new insights into the genomic architecture of high-risk CLL, define novel recurrent DNA copy number alterations and refine knowledge on del(9p), gain(8q) and alterations affecting NOTCH1 sig- naling. This study was registered at ClinicalTrials.gov with number NCT01392079.
Correspondence:
JENNIFER EDELMANN
jennifer.edelmann@uniklinik-ulm.de
Received: February 5, 2019. Accepted: August 23, 2019. Pre-published: August 29, 2019.
doi:10.3324/haematol.2019.217307
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/105/5/1379
©2020 Ferrata Storti Foundation
Material published in Haematologica is covered by copyright. All rights are reserved to the Ferrata Storti Foundation. Use of published material is allowed under the following terms and conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode. Copies of published material are allowed for personal or inter- nal use. Sharing published material for non-commercial pur- poses is subject to the following conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode, sect. 3. Reproducing and sharing published material for com- mercial purposes is not allowed without permission in writing from the publisher.
haematologica | 2020; 105(5)
1379
ARTICLE