Translocation t(14;19)(q32;q13) Is a Rare Abnormality in CLL and Associated with Trisomy 12, an Unmutated IgVH Status and a Distinct Gene Expression Profile.

Chronic lymphocytic leukemia (CLL) is a genetically heterogeneous disease. Recently, several genetic aberrations have been identified that allow to distinguish different biological subgroups within CLL. Translocation t(14;19)(q32;q13) leading to a fusion of IGH and BCL3 is a rare but recurrent abnormality in CLL and still poorly described. Based on karyotype data we identified 12 cases with t(14;19)(q32;q13) in a cohort of 1051 CLL (1.1%). In all these cases 1 to 10 chromosomal aberrations were observed in addition to t(14;19) (median: 3). Recurring accompanying aberrations were: +12 (n=8), loss of 18p (n=2), and gain of 10q (n=2). Interestingly, trisomy 12 is also the most frequent additional abnormality in CLL with t(14;18)(q32;q21). Remarkably, neither 13q deletions nor 11q deletions which are frequently observed in CLL overall, were found in addition to t(14;19). A TP53-deletion and a 6q21 deletion were observed in one case each. In 8/12 cases the mutation status of the immunoglobulin variable heavy chain gene (IgVH) was available. All 8 cases showed an unmutated IgVH status. Gene expression analysis (Affymetrix, HG U133 Plus 2.0) was performed in 9 cases with t(14;19) and compared to 44 cases with CLL comprising various chromosome aberrations excluding t(14;19). Using 10fold cross validation resulted in an assignment of 7 out of 9 cases with t(14;19) into the correct class, none of the cases without t(14;19) was classified into the t(14;19) group (accuracy 96%, sensitivity 78%, specificity 100%). Classification based on an independent test set led to comparable results (median accuracy 94%, sensitivity 67%, specificity 100%). The 10 most differentially expressed genes showing a higher expression in t(14;19)+ CLL were: TUBB6, CPSF6, RFC5, MAP3K8, CUGBP2, BCAT1, BCAT1, LOC647135, TSPAN13, SIGLEC6 and are involved in transition of mitotic cell cycle, DNA replication and RNA processing. The 10 most differentially expressed genes showing a lower expression in t(14;19)+ CLL were: LSR, APLP2, C2orf10, HS3ST1, LRRC32, PALM2-AKAP2, DFNB31, PDE4A, CTLA4, PDCD4 and are involved in signal transduction, apoptosis and immune response. In conclusion:

1. t(14;19)(q32;q13) is a rare, recurrent chromosome abnormality in CLL. It is very frequently accompanied by additional chromosomal aberrations. The most frequent additional aberration is trisomy 12.

2. t(14;19) is associated with an unmutated IgVH status.

3. Comparable to other translocations leading to fusion genes it is associated with a distinct gene expression profile.