BIRC3 alterations in chronic and B-cell acute lymphocytic leukemia patients

Abstract

Deletions within chromosome 11q22-23, are considered among the most common chromosomal aberrations in chronic lymphocytic leukemia (CLL), and are associated with a poor outcome. In addition to the ataxia telangiectasia mutated (<i>ATM</i>) gene, the baculoviral IAP repeat-containing 3 (<i>BIRC3</i>) gene is also located in the region. <i>BIRC3</i> encodes a negative regulator of the non-canonical nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) protein. Disruption of <i>BIRC3</i> is known to be restricted to CLL fludarabine-refractory patients. The aim of the present study was to determine the frequency of copy number changes of <i>BIRC3</i> and to assess its association with two known predictors of negative CLL outcome, <i>ATM</i> and tumor protein 53 (<i>TP53</i>) gene deletions. To evaluate the specificity of <i>BIRC3</i> alterations to CLL, <i>BIRC3</i> copy numbers were assessed in 117 CLL patients in addition to 45 B-cell acute lymphocytic leukemia (B-ALL) patients. A commercially available multiplex ligation dependent probe amplification kit, which includes four probes for the detection of <i>TP53</i> and four probes for <i>ATM</i> gene region, was applied. Interphase-directed fluorescence <i>in situ</i> hybridization was used to apply commercially available probes for <i>BIRC3</i>, <i>ATM</i> and <i>TP53</i>. High resolution array-comparative genomic hybridization was conducted in selected cases. Genetic abnormalities of <i>BIRC3</i> were detected in 23/117 (~20%) of CLL and 2/45 (~4%) of B-ALL cases. Overall, 20 patients with CLL and 1 with B-ALL possessed a <i>BIRC3</i> deletion, whilst 3 patients with CLL and 1 with B-ALL harbored a <i>BIRC3</i> duplication. All patients with an <i>ATM</i> deletion also carried a <i>BIRC3</i> deletion. Only 2 CLL cases possessed deletions in <i>BIRC3</i>, <i>ATM</i> and <i>TP53</i> simultaneously. Evidently, the deletion or duplication of <i>BIRC3</i> may be observed rarely in B-ALL patients. <i>BIRC3</i> duplication may occur in CLL patients, for which the prognosis requires additional studies in the future. The likelihood that <i>TP53</i> deletions occur simultaneously with <i>BIRC3</i> and/or <i>ATM</i> aberrations is low. However, as <i>ATM</i> deletions may, but not always, associate with <i>BIRC3</i> deletions, each region should be considered in the future diagnostics of CLL in order to aid treatment decisions, notably whether to treat with or without fludarabine.