Disruption of BIRC3 associates with fludarabine chemorefractoriness in TP53 wild-type chronic lymphocytic leukemia

Abstract

The genetic lesions identified to date do not fully recapitulate the molecular pathogenesis of chronic lymphocytic leukemia (CLL) and do not entirely explain the development of severe complications such as chemorefractoriness. In the present study, BIRC3, a negative regulator of noncanonical NF-B signaling, was investigated in different CLL clinical phases.

Chronic lymphocytic leukemia: Time to go past genomics?

“…Until recently the extent to which genetic aberrations contribute to NF-jB activation in CLL remained largely unknown except for low-frequency mutations in MYD88 and BIRC3 (noncanonical NF-jB pathway) genes. In CLL, 2 to 8% of cases harbor BIRC3 gene inactivation and are associated with poor clinical and genetic features [89]. BIRC3, in cooperation with TRAF2 and TRAF3, negatively regulates MAP3K14 that normally activates the non-canonical pathway of NF-jB signaling [90].…”

“…BIRC3, in cooperation with TRAF2 and TRAF3, negatively regulates MAP3K14 that normally activates the non-canonical pathway of NF-jB signaling [90]. BIRC3 mutations are predicted to truncate the C-terminal RING domain impairing the proteosomal degradation of MAP3K14 by BIRC3 and leading to constitutive NF-jB activation [89] (Fig. 3).…”

Clinical impact of recurrently mutated genes on lymphoma diagnostics: state-of-the-art and beyond

“…In CLL, besides TP53 and ATM mutations, which are both known to confer poor prognosis, recent high-throughput NGS studies have revealed recurrent mutations within NOTCH1, SF3B1, and BIRC3 for example, that were reported to be associated with poor clinical outcome with higher frequencies in relapsing/treatment-refractory CLL and in Richter's syndrome. 48,[69][70][71][72][73][74][75][76][77][78][79] More recent studies have also identified additional gene mutations that may confer a worse outcome in CLL, e.g. NKFBIE, EGR2, and RPS15, although they have been studied less.…”

Histologic transformation of chronic lymphocytic leukemia/small lymphocytic lymphoma

“…Several genes involved in a host of cellular and biological programs have been identified to be recurrently mutated in RS [40][41][42][43][44]. Genes involved in proliferation, apoptosis, and cell cycle regulation seem to stand out.…”