Genomic alterations in high-risk chronic lymphocytic leukemia frequently affect cell cycle key regulators and NOTCH1 regulated transcription.

Fiche publication

Date publication

août 2019

Journal

Haematologica

Auteurs

Membres identifiés du Cancéropôle Est :
Pr DELMER Alain

Tous les auteurs :
Edelmann J, Holzmann K, Tausch E, Saunderson EA, Jebaraj BMC, Steinbrecher D, Dolnik A, Blätte TJ, Landau DA, Saub J, Estenfelder S, Ibach S, Cymbalista F, Leblond V, Delmer A, Bahlo J, Robrecht S, Fischer K, Goede V, Bullinger L, Wu CJ, Mertens D, Ficz G, Gribben JG, Hallek M, Döhner H, Stilgenbauer S

Lien Pubmed

https://www.ncbi.nlm.nih.gov/pubmed/31467127

Résumé

To identify genomic alterations contributing to the pathogenesis of high risk chronic lymphocytic leukemia 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 chronic lymphocytic leukemia. In relapsed/refractory cases previously exposed to the selective pressure of chemo(immuno)therapy, gain(8)(q24.21) and del(9)(p21.3) were found particularly enriched. Both alterations affected 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 chronic lymphocytic leukemia (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 de repression of these NOTCH1 target genes particularly with SPEN mutations. In summary, we provide new insights into the genomic architecture of high risk chronic lymphocytic leukemia, define novel recurrent DNA copy number alterations and refine knowledge on del(9p), gain(8q) and alterations affecting NOTCH1 signaling. The study was registered at ClinicalTrials.gov with number NCT01392079.