Disruption of BIRC3 associates with fludarabine chemorefractoriness in TP53 wild-type chronic lymphocytic leukemia.
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-κB signaling, was investigated in different CLL clinical phases. BIRC3 lesions were absent in monoclonal B-cell lymphocytosis (0 of 63) and were rare in CLL at diagnosis (13 of 306, 4%). Conversely, BIRC3 disruption selectively affected 12 of 49 (24%) fludarabine-refractory CLL cases by inactivating mutations and/or gene deletions that distributed in a mutually exclusive fashion with TP53 abnormalities. In contrast to fludarabine-refractory CLL, progressive but fludarabine-sensitive patients were consistently devoid of BIRC3 abnormalities, suggesting that BIRC3 genetic lesions associate specifically with a chemorefractory phenotype. By actuarial analysis in newly diagnosed CLL (n = 306), BIRC3 disruption identified patients with a poor outcome similar to that associated with TP53 abnormalities and exerted a prognostic role that was independent of widely accepted clinical and genetic risk factors. Consistent with the role of BIRC3 as a negative regulator of NF-κB, biochemical studies revealed the presence of constitutive noncanonical NF-κB activation in fludarabine-refractory CLL patients harboring molecular lesions of BIRC3. These data identify BIRC3 disruption as a recurrent genetic lesion of high-risk CLL devoid of TP53 abnormalities.
Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy. rossidav@med.unipmn.it
Davide
D
Rossi
Marco
M
Fangazio
Silvia
S
Rasi
Tiziana
T
Vaisitti
Sara
S
Monti
Stefania
S
Cresta
Sabina
S
Chiaretti
Ilaria
I
Del Giudice
Giulia
G
Fabbri
Alessio
A
Bruscaggin
Valeria
V
Spina
Clara
C
Deambrogi
Marilisa
M
Marinelli
Rosella
R
Famà
Mariangela
M
Greco
Giulia
G
Daniele
Francesco
F
Forconi
Valter
V
Gattei
Francesco
F
Bertoni
Silvia
S
Deaglio
Laura
L
Pasqualucci
Anna
A
Guarini
Riccardo
R
Dalla-Favera
Robin
R
Foà
Gianluca
G
Gaidano
D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D015153:Blotting, Western; D004252:DNA Mutational Analysis; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics* / Q000378:metabolism; D053208:Kaplan-Meier Estimate; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism; D011379:Prognosis; D016016:Proportional Hazards Models; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D044767:Ubiquitin-Protein Ligases; D014740:Vidarabine / Q000031:analogs & derivatives* / Q000627:therapeutic use
D000970:Antineoplastic Agents; D051034:Inhibitor of Apoptosis Proteins; D016328:NF-kappa B; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C494832:BIRC3 protein, human; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D044767:Ubiquitin-Protein Ligases; D014740:Vidarabine; C024352:fludarabine