Edelmann, Jennifer, Holzmann, Karlheinz, Tausch, Eugen, Saunderson, Emily A., Jebaraj, Billy M. C., Steinbrecher, Daniela, Dolnik, Anna, Blaette, Tamara J., Landau, Dan A., Saub, Jenny, Estenfelder, Sven, Ibach, Stefan, Cymbalista, Florence, Leblond, Veronique, Delmer, Alain ORCID: 0000-0002-1430-2574, Bahlo, Jasmin, Robrecht, Sandra, Fischer, Kirsten, Goede, Valentin, Bullinger, Lars, Wu, Catherine J., Mertens, Daniel ORCID: 0000-0003-0227-7188, Ficz, Gabriella, Gribben, John G., Hallek, Michael, Doehner, Hartmut and Stilgenbauer, Stephan (2020). Genomic alterations in high-risk chronic lymphocytic leukemia frequently affect cell cycle key regulators and NOTCH1-regulated transcription. Haematologica, 105 (5). S. 1379 - 1391. PAVIA: FERRATA STORTI FOUNDATION. ISSN 0390-6078

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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 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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Edelmann, JenniferUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Holzmann, KarlheinzUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tausch, EugenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Saunderson, Emily A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jebaraj, Billy M. C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Steinbrecher, DanielaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dolnik, AnnaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Blaette, Tamara J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Landau, Dan A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Saub, JennyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Estenfelder, SvenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ibach, StefanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cymbalista, FlorenceUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Leblond, VeroniqueUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Delmer, AlainUNSPECIFIEDorcid.org/0000-0002-1430-2574UNSPECIFIED
Bahlo, JasminUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Robrecht, SandraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fischer, KirstenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Goede, ValentinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bullinger, LarsUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wu, Catherine J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mertens, DanielUNSPECIFIEDorcid.org/0000-0003-0227-7188UNSPECIFIED
Ficz, GabriellaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gribben, John G.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hallek, MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Doehner, HartmutUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stilgenbauer, StephanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-335568
DOI: 10.3324/haematol.2019.217307
Journal or Publication Title: Haematologica
Volume: 105
Number: 5
Page Range: S. 1379 - 1391
Date: 2020
Publisher: FERRATA STORTI FOUNDATION
Place of Publication: PAVIA
ISSN: 0390-6078
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
LONG NONCODING RNA; MUTATIONS; CLL; MYC; NOTCH1; TRANSFORMATION; PROGRESSION; SUPPRESSOR; RESISTANCE; EVOLUTIONMultiple languages
HematologyMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/33556

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