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

作者：Élise Chapiro, Élodie Pramil, M'boyba Khadija Diop, Damien Roos‐Weil, Clémentine Dillard, Clémentine Gabillaud, Karim Maloum, Catherine Settegrana, Lucile Baseggio, Jean‐François Lesesve, Mélanie Yon, Ludovic Jondreville, Claude Lesty, Frédéric Davi, Magali Le Garff‐Tavernier, Nathalie M Droin, Philippe Dessen, Caroline Algrin, Véronique Leblond, Jean Gabarre, Simon Bouzy, Virginie Éclache, Baptiste Gaillard, Evelyne Callet‐Bauchu, Marc Müller, Christine Lefebvre, Nathalie Nadal, Antoine Ittel, Stéphanie Struski, Marie‐Agnès Collonge‐Rame, Benoît Quilichini, Sandra Fert‐Ferrer, Nathalie Auger, Isabelle Radford‐Weiss, Lena Wagner, Sebastian Scheinost, Thorsten Zenz, Santos A. Susín, Olivier Bernard, Florence Nguyen‐Khac · 发表于：Blood · 年份：2019 · DOI：10.1182/blood.2019001187 · 被引用次数：51 · 研究领域：Chronic Lymphocytic Leukemia Research、Lymphoma Diagnosis and Treatment、Protein Degradation and Inhibitors

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 patients with 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) (P = .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...