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 (ATM) gene, the baculoviral IAP repeat-containing 3 (BIRC3) gene is also located in the region. BIRC3 encodes a negative regulator of the non-canonical nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) protein. Disruption of BIRC3 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 BIRC3 and to assess its association with two known predictors of negative CLL outcome, ATM and tumor protein 53 (TP53) gene deletions. To evaluate the specificity of BIRC3 alterations to CLL, BIRC3 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 TP53 and four probes for ATM gene region, was applied. Interphase-directed fluorescence in situ hybridization was used to apply commercially available probes for BIRC3, ATM and TP53. High resolution array-comparative genomic hybridization was conducted in selected cases. Genetic abnormalities of BIRC3 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 BIRC3 deletion, whilst 3 patients with CLL and 1 with B-ALL harbored a BIRC3 duplication. All patients with an ATM deletion also carried a BIRC3 deletion. Only 2 CLL cases possessed deletions in BIRC3, ATM and TP53 simultaneously. Evidently, the deletion or duplication of BIRC3 may be observed rarely in B-ALL patients. BIRC3 duplication may occur in CLL patients, for which the prognosis requires additional studies in the future. The likelihood that TP53 deletions occur simultaneously with BIRC3 and/or ATM aberrations is low. However, as ATM deletions may, but not always, associate with BIRC3 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.

E3 Ligase cIAP2 Mediates Downregulation of MRE11 and Radiosensitization in Response to HDAC Inhibition in Bladder Cancer

“…As cIAP2 contains a caspase recruitment and activation domain (CARD) and is known to bind caspases in a noninhibitory manner (27) there is the possibility of linkage between cIAP2 and the formation of the MRE11 truncation via caspase pathways, for example if DNA repair is not required when caspases are activated for apoptosis, the truncation may accelerate MRE11 degradation. The cIAP2-MALT1 fusion protein has been shown to play a role in many cancers, via the paracaspase function of MALT1 (49) and cIAP2 is often mutated in cancers where ATM is mutated, further suggesting a role in regulation of DNA damage and repair (19). Proteasomal inhibition does not prevent the formation of the truncation, confirming it is generated by a protease distinct from the proteasome.…”

“…IAP family members have been shown to have a pivotal role in intrinsic and extrinsic cell death pathways, and are key players in the regulation of NF-kB signaling via the ripoptosome and the innate immune response (18). cIAP2 is a biomarker for acute lymphocytic leukemia outcome (19), although the precise function and substrate specificity of cIAP2 is unclear due to redundancy with cIAP1 in cell death and NF-kB regulation.…”

Identification of microRNA-124 in regulation of Hepatocellular carcinoma through BIRC3 and the NF-κB pathway

“…BIRC3 exerts a functional role in many malignancies, including oral squamous cell carcinoma, glioblastoma, pancreatic cancer. In addition, it plays an important role in regulating nuclear factor-κB (NF-κB) signaling pathway, which is involved in the development of cancer 11 , 12 .…”

Regulation of apoptosis by E3 ubiquitin ligases in ubiquitin proteasome system

“…BIRC3 was shown to be upregulated in response to irradiation and temozolomide treatment (Wang et al, ). In addition, BIRC3 has also been shown to play a role in chronic lymphocytic leukaemia (Alhourani et al, ). Table enlists E3 ubiquitin ligases and their substrates (proteins from apoptosis pathway).…”