Genetic characterization of B-cell prolymphocytic leukemia: A prognostic model involving MYC and TP53

Elise Chapiro, Elodie Pramil, M'Boyba Diop, Damien Roos-Weil, Clémentine Dillard, Clémentine Gabillaud, Karim Maloum, Catherine Settegrana, Lucile Baseggio, Jean Franćois Lesesve, Mélanie Yon, Ludovic Jondreville, Claude Lesty, Frédéric Davi, Magali Le Garff-Tavernier, Nathalie Droin, Philippe Dessen, Caroline Algrin, Véronique Leblond, Jean GabarreSimon Bouzy, Virginie Eclache, Baptiste Gaillard, Evelyne Callet-Bauchu, Marc Muller, Christine Lefebvre, Nathalie Nadal, Antoine Ittel, Stéphanie Struski, Marie Agnés Collonge-Rame, Benoit Quilichini, Sandra Fert-Ferrer, Nathalie Auger, Isabelle Radford-Weiss, Lena Wagner, Sebastian Scheinost, Thorsten Zenz, Santos A. Susin, Olivier A. Bernard, Florence Nguyen-Khac

    Résultats de recherche: Contribution à un journalArticleRevue par des pairs

    35 Citations (Scopus)

    Résumé

    B-cell prolymphocytic leukemia (B-PLL) is a rare hematological disorder whose underlying oncogenic mechanisms are poorly understood. Our cytogenetic and molecular assessments of 34 patientswith B-PLL revealed several disease-specific features and potential therapeutic targets. The karyotype was complex (≥3 abnormalities) in 73% of the patients and highly complex (≥5 abnormalities) in 45%. The most frequent chromosomal aberrations were translocations involving MYC [t(MYC)] (62%), deletion (del)17p (38%), trisomy (tri)18 (30%), del13q (29%), tri3 (24%), tri12 (24%), and del8p (23%). Twenty-six (76%) of the 34 patients exhibited an MYC aberration, resulting from mutually exclusive translocations or gains.Whole-exome sequencing revealed frequent mutations in TP53, MYD88, BCOR, MYC, SF3B1, SETD2, CHD2, CXCR4, and BCLAF1. The majority of B-PLL used the IGHV3 or IGHV4 subgroups (89%) and displayed significantly mutated IGHV genes (79%). We identified 3 distinct cytogenetic risk groups: Low risk (no MYC aberration), intermediate risk (MYC aberration but no del17p), and high risk (MYC aberration and del17p) (P5.0006). In vitro drug response profiling revealed that the combination of a B-cell receptor or BCL2 inhibitor with OTX015 (a bromodomain and extra-terminal motif inhibitor targeting MYC) was associated with significantly lower viability of B-PLL cells harboring a t(MYC). We concluded that cytogenetic analysis is a useful diagnostic and prognostic tool in B-PLL. Targeting MYC may be a useful treatment option in this disease.

    langue originaleAnglais
    Pages (de - à)1821-1831
    Nombre de pages11
    journalBlood
    Volume134
    Numéro de publication21
    Les DOIs
    étatPublié - 21 nov. 2019

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