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Editorials
the BIRC3-Map3K14 interaction for activation of the non-canonical NFκB pathway. Silencing Map3K14 by short hairpin RNA decreased the levels of NFκB, which was followed by reduced viability of BIRC3-mutated cells. MAP3K14 could, therefore, be a potential drug tar- get to overcome mutant BIRC3-induced cell proliferation. Next Diop and colleagues evaluated the vulnerability of BIRC3-mutated cell lines and primary CLL cells to flu- darabine. Viability assays under fludarabine treatment confirmed that BIRC3-mutated samples had a higher via- bility than BIRC3 wildtype ones, although still lower than that of TP53-mutated samples after 48 h. Therefore, refractoriness to fludarabine, which has been consistently assigned to TP53 defects in previous clinical and biologi- cal studies, is also found to a lesser extent in BIRC3- mutated cells. This translates into a significantly shorter progression-free survival of patients with BIRC3-mutated CLL receiving therapy with fludarabine, cyclophos- phamide and rituximab (FCR), as found by the authors in a cohort of 287 previously untreated CLL patients.
This effect on outcome may be different with more modern treatment regimens. Although Diop and col- leagues provide some evidence that NFκB in BIRC3- mutated patients remains active with ibrutinib therapy, there are more downstream targets of Bruton tyrosine kinase (BTK), including MEK/ERK and MAPK, which should remain inhibited by ibrutinib.10 In general, in vitro cultures are less informative regarding the efficacy of BTK inhibitors for which the microenvironment plays a crucial role. In contrast to ibrutinib, treatment with venetoclax resulted in a similarly low viability of BIRC3-mutated and wildtype primary CLL cells.9 This appears rational, as BCL2 is not involved in the non-canonical pathway affected by BIRC3. However, there is also some evidence that BCL2 levels are higher in BIRC3-mutated cases, indi- cating a greater sensitivity to venetoclax.11 Although only limited data on the impact of BIRC3 mutations are avail- able from clinical trials with ibrutinib and venetoclax, an adverse outcome has not been observed, in contrast to del17p/mutated TP53.12,13
Despite the comprehensive work by Diop and col- leagues some questions remain in addition to the unclear impact on outcome with novel compounds. This include the difference between monoallelic and biallelic defects (i.e., mutations and deletions), which considered together should result in a much higher number of affected
patients. Furthermore the role of non-truncating missense variants and mutations outside the C-terminal RING- domain found predominantly in solid tumors, but also in lymphomas and CLL, remains unclear. Therefore, further studies, in particular in cohorts of patients from prospec- tive trials evaluating biologically targeted agents, are war- ranted before BIRC3 assessment can be put forward as a routine test in general clinical practice.
References
1. Rose-Zerilli MJJ, Forster J, Parker H, et al. ATM mutation rather than BIRC3 deletion and/or mutation predicts reduced survival in 11q- deleted chronic lymphocytic leukemia: data from the UK LRF CLL4 trial. Haematologica. 2014;99(4):736-742.
2. RossiD,BruscagginA,SpinaV,etal.MutationsoftheSF3B1splicing factor in chronic lymphocytic leukemia: association with progres- sion and fludarabine-refractoriness. Blood. 2011;118(26):6904-6908.
3. Landau DA, Tausch E, Taylor-Weiner AN, et al. Mutations driving CLL and their evolution in progression and relapse. Nature. 2015;526(7574):525-530.
4. Nadeu F, Delgado J, Royo C, et al. Clinical impact of clonal and sub- clonal TP53, SF3B1, BIRC3, NOTCH1, and ATM mutations in chronic lymphocytic leukemia. Blood. 2016;127(17):2122-2130.
5. Baliakas P, Hadzidimitriou A, Sutton L-A, et al. Recurrent mutations refine prognosis in chronic lymphocytic leukemia. Leukemia. 2015;29(2):329-336.
6. Rossi D, Fangazio M, Rasi S, et al. Disruption of BIRC3 associates with fludarabine chemorefractoriness in TP53 wild-type chronic lymphocytic leukemia. Blood. 2012;119(12):2854-2862.
7. Zarnegar BJ, Wang Y, Mahoney DJ, et al. Noncanonical NF-kappaB activation requires coordinated assembly of a regulatory complex of the adaptors cIAP1, cIAP2, TRAF2 and TRAF3 and the kinase NIK. Nat Immunol. 2008;9(12):1371-1378.
8. Rickert RC, Jellusova J, Miletic AV. Signaling by the tumor necrosis factor receptor superfamily in B-cell biology and disease. Immunol Rev. 2011;244(1):115-133.
9. Diop F, Moia R, Favini C, et al. Biological and clinical implications of BIRC3 mutations in chronic lymphocytic leukemia. Haematologica 2020;105(2):448-456.
10. Cheng S, Ma J, Guo A, et al. BTK inhibition targets in vivo CLL pro- liferation through its effects on B-cell receptor signaling activity. Leukemia. 2014;28(3):649-657.
11. AsslaberD,WachtN,LeischM,etal.BIRC3expressionpredictsCLL progression and defines treatment sensitivity via enhanced NF-κB nuclear translocation. Clin Cancer Res. 2019;25(6):1901-1912.
12. Tausch E, Bahlo J, Robrecht S, et al. Genetic markers and outcome in the CLL14 trial of the GCLLSG comparing front line obinutuzumab plus chlorambucil or venetoclax in patients with comorbidity. Hematol Oncol. 2019;37(S2):84-86.
13. Brown JR, Hillmen P, O’Brien S, et al. Extended follow-up and impact of high-risk prognostic factors from the phase 3 RESONATE study in patients with previously treated CLL/SLL. Leukemia. 2018;32(1):83-91.
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