title: Distinct patterns of novel gene mutations in poor-prognostic stereotyped subsets of chronic lymphocytic leukemia: the case of SF3B1 and subset #2.
abstract: Recent studies have revealed recurrent mutations of the NOTCH1, SF3B1 and BIRC3 genes in chronic lymphocytic leukemia (CLL), especially among aggressive, chemorefractory cases. Nevertheless, it is currently unknown whether their presence may differ in subsets of patients carrying stereotyped B-cell receptors and also exhibiting distinct prognoses. Here, we analyzed the mutation status of NOTCH1, SF3B1 and BIRC3 in three subsets with particularly poor prognosis, that is, subset #1, #2 and #8, aiming to explore links between genetic aberrations and immune signaling. A remarkably higher frequency of SF3B1 mutations was revealed in subset #2 (44%) versus subset #1 and #8 (4.6% and 0%, respectively; P<0.001). In contrast, the frequency of NOTCH1 mutations in subset #2 was only 8%, lower than the frequency observed in either subset #1 or #8 (19% and 14%, respectively; P=0.04 for subset #1 versus #2). No associations were found for BIRC3 mutations that overall were rare. The apparent non-random association of certain mutations with stereotyped CLL subsets alludes to subset-biased acquisition of genomic aberrations, perhaps consistent with particular antigen/antibody interactions. These novel findings assist in unraveling specific mechanisms underlying clinical aggressiveness in poor-prognostic stereotyped subsets, with far-reaching implications for understanding their clonal evolution and implementing biologically oriented therapy.
authors.affiliation: Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, UK.
authors.forename: J C
authors.initials: JC
authors.lastname: Strefford
authors.forename: L-A
authors.initials: LA
authors.lastname: Sutton
authors.forename: P
authors.initials: P
authors.lastname: Baliakas
authors.forename: A
authors.initials: A
authors.lastname: Agathangelidis
authors.forename: J
authors.initials: J
authors.lastname: Malčíková
authors.forename: K
authors.initials: K
authors.lastname: Plevova
authors.forename: L
authors.initials: L
authors.lastname: Scarfó
authors.forename: Z
authors.initials: Z
authors.lastname: Davis
authors.forename: E
authors.initials: E
authors.lastname: Stalika
authors.forename: D
authors.initials: D
authors.lastname: Cortese
authors.forename: N
authors.initials: N
authors.lastname: Cahill
authors.forename: L B
authors.initials: LB
authors.lastname: Pedersen
authors.forename: P F
authors.initials: PF
authors.lastname: di Celle
authors.forename: T
authors.initials: T
authors.lastname: Tzenou
authors.forename: C
authors.initials: C
authors.lastname: Geisler
authors.forename: P
authors.initials: P
authors.lastname: Panagiotidis
authors.forename: A W
authors.initials: AW
authors.lastname: Langerak
authors.forename: N
authors.initials: N
authors.lastname: Chiorazzi
authors.forename: S
authors.initials: S
authors.lastname: Pospisilova
authors.forename: D
authors.initials: D
authors.lastname: Oscier
authors.forename: F
authors.initials: F
authors.lastname: Davi
authors.forename: C
authors.initials: C
authors.lastname: Belessi
authors.forename: L
authors.initials: L
authors.lastname: Mansouri
authors.forename: P
authors.initials: P
authors.lastname: Ghia
authors.forename: K
authors.initials: K
authors.lastname: Stamatopoulos
authors.forename: R
authors.initials: R
authors.lastname: Rosenquist
mesh_terms: D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D014408:Biomarkers, Tumor / Q000235:genetics*; D015331:Cohort Studies; D004273:DNA, Neoplasm / Q000235:genetics; D005500:Follow-Up Studies; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000145:classification* / Q000235:genetics* / Q000401:mortality; D009154:Mutation / Q000235:genetics*; D010750:Phosphoproteins / Q000235:genetics*; D016133:Polymerase Chain Reaction; D011379:Prognosis; D000072260:RNA Splicing Factors; D051881:Receptor, Notch1 / Q000235:genetics*; D017413:Ribonucleoprotein, U2 Small Nuclear / Q000235:genetics*; D015996:Survival Rate; D044767:Ubiquitin-Protein Ligases
chemical_list: D014408:Biomarkers, Tumor; D004273:DNA, Neoplasm; D051034:Inhibitor of Apoptosis Proteins; C497761:NOTCH1 protein, human; D010750:Phosphoproteins; D000072260:RNA Splicing Factors; D051881:Receptor, Notch1; D017413:Ribonucleoprotein, U2 Small Nuclear; C112491:SF3B1 protein, human; C494832:BIRC3 protein, human; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D044767:Ubiquitin-Protein Ligases