Page 21 - 2020_02-Haematologica-web

Editorials
BIRC3 mutations in chronic lymphocytic leukemia – uncommon and unfavorable
Eugen Tausch and Stephan Stilgenbauer
Department of Internal Medicine III, Ulm University, Ulm, Germany
E-mail: STEPHAN STILGENBAUER - stephan.stilgenbauer@uniklinik-ulm.de
doi:10.3324/haematol.2019.238691
Chronic lymphocytic leukemia (CLL) is character- ized by recurrent genomic aberrations as well as gene mutations, and BIRC3 (Baculoviral IAP Repeat Containing 3, also called cIAP2) can be affected by both. BIRC3 is located on chromosome 11 in proximity to ATM and 11q deletions include the BIRC3 locus in approx- imately 80% of cases.1 In addition, BIRC3 can be affected by mutations, mainly nonsense and frameshift variants, with an incidence of 3-5% in untreated patients, making such mutations rare in comparison to TP53, NOTCH1, SF3B1 or ATM defects.1–5 However, as the frequency in flu- darabine-refractory cohorts is higher, BIRC3 abnormalities were discussed to define a high-risk group of CLL patients. Indeed BIRC3 did turn out to have an adverse prognostic impact in some chemotherapy-treated CLL cohorts.1,6 Furthermore, BIRC3 abnormalities are associat-
ed with worse outcome in other lymphomas, acute lym- phoblastic leukemia and solid tumors, including brain tumors in which BIRC3 is reported to induce malignant transformation of low-grade gliomas to glioblastomas.6–8
While some studies have provided evidence of a clinical impact of mutated BIRC3 and others have not, the func- tional implications of BIRC3 deletion or mutation are par- tially unexplored. BIRC3 induces proteasomal degrada- tion of MAP3K14, which is the major driver of non- canonical nuclear factor kappaB (NFκB) activation. Therefore, disrupted BIRC3 could result in a ligand-inde- pendent activation of the constitutive NFκB pathway, inducing cell proliferation and survival.7,8 At this point Diop and colleagues began their functional characteriza- tion of BIRC3 mutations in CLL as described in this issue of Haematologica.9 First they confirmed the importance of
Figure 1. The canonical and non-canonical nuclear factor kappaB pathways. In the canonical nuclear factor kappaB (NFκB) pathway, activation of the B-cell receptor (BCR) results in a shift of the transcription factors c-Rel, p65 and p50 to the nucleus if not sequestered by IKB. In the non-anonical pathway, activation of MAP3K14 results in proteolytic cleavage of p100 to p52, which as a heterodimer with Rel-B serves as a transcription regulator. BIRC3, which is part of the negative regulatory complex, induces proteosomal degradation of MAP3K14, the major driver of activation of the non-canonical NFκB pathway.
haematologica | 2020; 105(2)
255