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

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 (5 abnormalities) in 45%. The most frequent chromosomal aberrations were translocations involving [t()] (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 aberration, resulting from mutually exclusive translocations or gains. Whole-exome sequencing revealed frequent mutations in , , , , , , , , and The majority of B-PLL used the or subgroups (89%), and displayed significantly mutated genes (79%). We identified three distinct cytogenetic risk groups: low-risk (no aberration), intermediate-risk ( aberration but no del17p), and high-risk ( aberration and del17p) (p=.0006). 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 ) was associated with significantly lower viability of B-PLL cells harboring a t(). We conclude that cytogenetic analysis is a useful diagnostic and prognostic tool in B-PLL. Targeting may be a useful treatment option in this disease.