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

• Published in: Blood Vol. 134; no. 21; pp. 1821 - 1831
• Main Authors: Chapiro, Elise, Pramil, Elodie, Diop, M'boyba, Roos-Weil, Damien, Dillard, Clémentine, Gabillaud, Clémentine, Maloum, Karim, Settegrana, Catherine, Baseggio, Lucile, Lesesve, Jean-François, Yon, Mélanie, Jondreville, Ludovic, Lesty, Claude, Davi, Frédéric, Le Garff-Tavernier, Magali, Droin, Nathalie, Dessen, Philippe, Algrin, Caroline, Leblond, Véronique, Gabarre, Jean, Bouzy, Simon, Eclache, Virginie, Gaillard, Baptiste, Callet-Bauchu, Evelyne, Muller, Marc, Lefebvre, Christine, Nadal, Nathalie, Ittel, Antoine, Struski, Stéphanie, Collonge-Rame, Marie-Agnès, Quilichini, Benoit, Fert-Ferrer, Sandra, Auger, Nathalie, Radford-Weiss, Isabelle, Wagner, Lena, Scheinost, Sebastian, Zenz, Thorsten, Susin, Santos A., Bernard, Olivier A., Nguyen-Khac, Florence
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 21-11-2019; American Society of Hematology
• Subjects: Aged; Aged, 80 and over; Chromosome Aberrations; Cytogenetic Analysis; Female; Hematology; Human health and pathology; Humans; Leukemia, Prolymphocytic, B-Cell - genetics; Life Sciences; Male; Middle Aged; Prognosis; Proto-Oncogene Proteins c-myc - genetics; Tumor Suppressor Protein p53 - genetics
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.2019001187

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 may be a useful treatment option in this disease.
•B-PLL is tightly linked to MYC aberrations (translocation or gain) and 17p (TP53) deletion.•Cases of B-PLL with MYC aberration and 17p (TP53) deletion have the worst prognosis.
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