Genomic alterations in high-risk chronic lymphocytic leukemia frequently affect cell cycle key regulators and NOTCH1-regulated transcription
| Autor: | Eugen Tausch, Alain Delmer, Sandra Robrecht, Karlheinz Holzmann, Florence Cymbalista, Valentin Goede, Stephan Stilgenbauer, Tamara J. Blätte, Jenny Saub, Gabriella Ficz, Daniela Steinbrecher, Anna Dolnik, Hartmut Döhner, Billy Michael Chelliah Jebaraj, Stefan Ibach, Véronique Leblond, Dan A. Landau, John G. Gribben, Daniel Mertens, Jennifer Edelmann, Emily A. Saunderson, Catherine J. Wu, Sven Estenfelder, Kirsten Fischer, Lars Bullinger, Jasmin Bahlo, Michael Hallek |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Cancer Research
Chronic lymphocytic leukemia Single-nucleotide polymorphism Biology 03 medical and health sciences 0302 clinical medicine CDKN2A hemic and lymphatic diseases medicine Humans Chronic Lymphocytic Leukemia Prospective Studies HES1 Receptor Notch1 Enhancer Gene RBPJ Cell Cycle Editorials Hematology Articles Genomics Cell cycle medicine.disease Leukemia Lymphocytic Chronic B-Cell Mutation Cancer research Immunotherapy Rituximab 030215 immunology |
| Zdroj: | Haematologica |
| Popis: | 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 analyzed 75 relapsed/refractory and 71 treatment-naive 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-naive 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 particularly enriched. Both alterations affect key regulators of cell-cycle progression, 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 target 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 summary, 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 signaling. This study was registered at ClinicalTrials.gov with number NCT01392079. |
| Databáze: | OpenAIRE |
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