GRCh38 · COSMIC v99


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Genetic characterization of B-cell prolymphocytic leukemia: a prognostic model involving MYC and TP53.
Paper ID
Chapiro E, Pramil E, Diop M, Roos-Weil D, Dillard C, Gabillaud C, Maloum K, Settegrana C, Baseggio L, Lesesve JF, Yon M, Jondreville L, Lesty C, Davi FB, Le Garff-Tavernier M, Droin NM, Dessen P, Algrin C, Leblond V, Gabarre J, Bouzy S, Eclache V, Gaillard B, Callet-Bauchu E, Muller M, Lefebvre C, Nadal N, Ittel A, Struski S, Collonge-Rame MA, Quilichini B, Fert-Ferrer S, Auger N, Radford-Weiss I, Wagner L, Scheinost S, Zenz T, Susin SA, Bernard OA and Nguyen-Khac F
AP-HP, France.
Blood, 2019
ISSN: 1528-0020
PMID: 31527074 (view at PubMed or Europe PMC)
B-cell prolymphocytic leukemia (B-PLL) is a rare hematological disorder whose underlying oncogenic mechanisms are poorly understood. Our cytogenetic and molecular assessment of 34 patients with B-PLL revealed several disease-specific features and potential therapeutic targets. The karyotype was complex ({greater than or equal to}3 abnormalities) in 73% of the patients and highly complex (<u>&gt;</u>5 abnormalities) in 45%. The most frequent chromosomal aberrations were translocations involving <i>MYC</i> [t(<i>MYC</i>)] (62%), deletion (del)17p (38%), trisomy (tri)18 (30%), del13q (29%), tri3 (24%), tri12 (24%), and del8p (23%). Twenty-six of the 34 patients (76%) exhibit <i>MYC</i> aberration, resulting from mutually exclusive translocations or gains. Whole-exome sequencing revealed frequent mutations in <i>TP53</i>, <i>MYD88</i>, <i>BCOR</i>, <i>MYC</i>, <i>SF3B1</i>, <i>SETD2</i>, <i>CHD2</i>, <i>CXCR4</i>, and <i>BCLAF1</i> The majority of B-PLL used the <i>IGHV3</i> or <i>IGHV4</i> subgroups (89%), and displayed significantly mutated <i>IGHV</i> genes (79%). We identified three distinct cytogenetic risk groups: low-risk (no <i>MYC</i> aberration), intermediate-risk (<i>MYC</i> aberration but no del17p), and high-risk (<i>MYC</i> aberration and del17p) (p=.0006). <i>In vitro</i> drug response profiling revealed that the combination of a B-cell receptor or BCL2 inhibitor with OTX015 (a bromodomain and extra-terminal motif (BET) inhibitor targeting <i>MYC</i>) was associated with significantly lower viability of B-PLL cells harboring a t(<i>MYC</i>). We conclude that cytogenetic analysis is a useful diagnostic and prognostic tool in B-PLL. Targeting <i>MYC</i> may be a useful treatment option in this disease.
Paper Status