BIRC3 – Chronic Lymphocytic Leukemia

Chronic lymphocytic leukemia (CLL) is the most common adult leukemia and is driven by recurrent somatic alterations in multiple signaling and apoptotic regulators. BIRC3, encoding an inhibitor of apoptosis protein that normally restrains noncanonical NF-κB signaling, is recurrently inactivated in CLL, particularly in cases with 11q deletions. Somatic BIRC3 lesions include monoallelic deletions in the del(11q) region and truncating mutations in the remaining allele, leading to aberrant NF-κB2 activation and apoptotic resistance.

Genetic screening across large cohorts has identified BIRC3 mutations in 2.5% of 919 unselected CLL patients and in 4.2% of 406 untreated cases, often co-occurring with unmutated IGHV status and del(11q) ([PMID:24943832]; [PMID:26837699]). In del(11q) CLL, monoallelic BIRC3 loss occurs in up to 80% of cases, with biallelic inactivation in a subset, confirming allelic-dose dependency of noncanonical NF-κB pathway activation ([PMID:34244476]).

Functional evidence demonstrates that BIRC3 disruption stabilizes NIK, promotes RelB-p52 nuclear translocation, and decreases sensitivity to fludarabine in cell lines and primary CLL samples. In a retrospective cohort of 287 first-line FCR-treated patients, BIRC3 mutations defined a subgroup with median progression-free survival of 2.2 years (P < 0.001), similar to TP53-mutant cases, and remained an independent predictor of poor outcome (HR 2.8, P = 0.004) ([PMID:31371416]).

No studies have reported germline segregation of BIRC3 variants, consistent with a somatic oncogenic mechanism. Although the overall mutation frequency is modest, the reproducibility of associations across independent cohorts and concordant functional data support a moderate clinical validity for the BIRC3–CLL relationship.

In summary, recurrent somatic BIRC3 inactivation contributes to CLL pathogenesis via noncanonical NF-κB activation and predicts fludarabine resistance and inferior survival. Routine assessment of BIRC3 status may enhance risk stratification and guide therapeutic decisions in CLL.

References

• Leukemia • 2015 • Recurrent mutations refine prognosis in chronic lymphocytic leukemia. PMID:24943832
• Blood • 2016 • Clinical impact of clonal and subclonal TP53, SF3B1, BIRC3, NOTCH1, and ATM mutations in chronic lymphocytic leukemia. PMID:26837699
• Haematologica • 2020 • Biological and clinical implications of BIRC3 mutations in chronic lymphocytic leukemia. PMID:31371416
• Blood Cancer Journal • 2021 • Biological significance of monoallelic and biallelic BIRC3 loss in del(11q) chronic lymphocytic leukemia progression. PMID:34244476

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