Page 219 - 2020_02-Haematologica-web

BIRC3 mutations in CLL
boring TP53 disruption (Figure 6B). Consistently, BIRC3- mutated patients had a lower likelihood of achieving complete response (22.2%) at the end of FCR compared to BIRC3-wildtype cases (76.7%; P=0.001). Well-known molecular prognostic biomarkers of CLL, such as unmu- tated IGHV gene status and 17p deletion also associated with a significantly shorter PFS, supporting the represen- tativeness of the study cohort (Table 2). By multivariate analysis including variables showing a multiplicity- adjusted significant association with PFS, BIRC3 muta- tions maintained an independent association with PFS, with a hazard ratio of 2.8 (95% confidence interval: 1.4- 5.6; P=0.004) (Table 2).
Discussion
The results of this study provide evidence that: (i) BIRC3 mutations are associated with activation of the non- canonical NF-κB pathway and with resistance to fludara- bine in vitro; and (ii) BIRC3-mutated patients, like cases harboring TP53 disruption, are subject to failure of FCR chemoimmunotherapy.
The mere presence of somatic mutations is insufficient
to implicate a gene in cancer. Cancer geneticists and bioin- formaticians differentiate “passenger” events, likely being randomly acquired, to distinguish them from mutations targeting candidate “cancer-driver” genes, likely implicat- ed in the tumor biology, according to a statistical defini- tion. Any given gene is labeled as a candidate “cancer driv- er” if it harbors somatic point mutations at a statistically significant rate or pattern in cancer samples. In CLL, more than 40 genes fulfill the statistical definition of a candidate “cancer driver”, including BIRC3, but few of them are bio- logically validated (i.e. SF3B1, NOTCH1, TP53, ATM, FBXW7).6,7,17-20 The BIRC3 gene codes for a protein that ubiquitinates and negatively regulates the central activat- ing kinase of the non-canonical NF-κB pathway, namely MAP3K14 (also known as NIK).21,22 In lymphoid malignan- cies, the NF-κB pathway is a pivotal and positive mediator of cell proliferation and survival.5,23,24 With regards to CLL, BIRC3 mutations are absent in patients with monoclonal B-cell lymphocytosis, are rare at the time of diagnosis (3- 4%), but are detectable in approximately 25% of fludara- bine-refractory patients.13 In this study, we verified the biological consequences of BIRC3 mutations, showing that they are associated with activation of the non-canon- ical NF-κB pathway, that BIRC3-mutated lymphoid cells
AB
CD
Figure 4. Responses of primary cells lines to fludarabine and venetoclax. (A-D) Viability of BIRC3-mutated (n=6 patients, red line), TP53-mutated (n=8 patients, black line) and wildtype (n=7 patients, blue line) primary CLL cells treated with different concentrations of fludarabine for 24 h (A) and 48 h (B) or venetoclax for 24 h (C) and 48 h (D). The pairwise P values are listed in the tables below the respective figures. M, mutated; WT, wildtype; NT, not treated.
haematologica | 2020; 105(2)
453