Abstract

BIRC3 is a recurrently mutated gene in chronic lymphocytic leukemia (CLL) but the functional implications of BIRC3 mutations are largely unexplored. Furthermore, little is known about the prognostic impact of BIRC3 mutations in CLL cohorts homogeneously treated with first-line fludarabine, cyclophosphamide, and rituximab (FCR). By immunoblotting analysis, we showed that the non-canonical nuclear factor-êB pathway is active in BIRC3-mutated cell lines and in primary CLL samples, as documented by the stabilization of MAP3K14 and by the nuclear localization of p52. In addition, BIRC3-mutated primary CLL cells are less sensitive to fludarabine. In order to confirm in patients that BIRC3mutations confer resistance to fludarabine-based chemoimmunotherapy, a retrospective multicenter cohort of 287 untreated patients receiving first-line FCR was analyzed by targeted next-generation sequencing of 24 recurrently mutated genes in CLL. By univariate analysis adjusted for multiple comparisons BIRC3mutations identify a poor prognostic subgroup of patients in whom FCR treatment fails (median progression-free survival: 2.2 years, P
Original languageEnglish
Pages (from-to)448-456
Number of pages9
JournalHaematologica
Volume105
Issue number2
DOIs
Publication statusPublished - 2020

Keywords

  • baculoviral IAP repeat containing protein 3
  • cyclophosphamide
  • fludarabine
  • ibrutinib
  • immunoglobulin enhancer binding protein
  • protein p52
  • rituximab
  • Article
  • baculoviral IAP repeat containing protein 3 gene
  • cell viability
  • chronic lymphatic leukemia
  • cohort analysis
  • female
  • gene
  • gene expression
  • gene mutation
  • high throughput sequencing
  • human
  • human cell
  • immunoblotting
  • major clinical study
  • male
  • multicenter study
  • nuclear localization signal
  • progression free survival
  • retrospective study
  • risk factor
  • Western blotting
  • Z-138 cell line

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