Distinct patterns of novel gene mutations in poor-prognostic stereotyped subsets of chronic lymphocytic leukemia: the case of SF3B1 and subset #2

• Published in: Leukemia Vol. 27; no. 11; pp. 2196 - 2199
• Main Authors: Strefford, J C, Sutton, L-A, Baliakas, P, Agathangelidis, A, Malčíková, J, Plevova, K, Scarfó, L, Davis, Z, Stalika, E, Cortese, D, Cahill, N, Pedersen, L B, di Celle, P F, Tzenou, T, Geisler, C, Panagiotidis, P, Langerak, A W, Chiorazzi, N, Pospisilova, S, Oscier, D, Davi, F, Belessi, C, Mansouri, L, Ghia, P, Stamatopoulos, K, Rosenquist, R
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-11-2013; Nature Publishing Group
• Subjects: 631/208/737; 692/699/67/1990/283/1895; 692/700/1750; Aggressiveness; Antibodies; Antigens; Baculoviral IAP Repeat-Containing 3 Protein; Biomarkers, Tumor - genetics; Cancer; Cancer Research; Chronic lymphocytic leukemia; Cohort Studies; Critical Care Medicine; DNA methylation; DNA, Neoplasm - genetics; Evolution; Follow-Up Studies; Gene mutations; Genes; Genetic aspects; Hematology; Hospitals; Humans; Identification and classification; immunoglobulin genes; Immunoglobulins; Immunology; Inhibitor of Apoptosis Proteins - genetics; Intensive; Internal Medicine; Leukemia; Leukemia, Lymphocytic, Chronic, B-Cell - classification; Leukemia, Lymphocytic, Chronic, B-Cell - genetics; Leukemia, Lymphocytic, Chronic, B-Cell - mortality; Lymphatic leukemia; Lymphocytes B; Medical prognosis; Medicin och hälsovetenskap; Medicine; Medicine & Public Health; Mutation; Mutation - genetics; Neoplastic processes; NOTCH1 mutations; Notch1 protein; Oncology; original-article; Pathology; Phosphoproteins - genetics; Polymerase Chain Reaction; Prognosis; Receptor, Notch1 - genetics; Ribonucleoprotein, U2 Small Nuclear - genetics; RNA Splicing Factors; SF3B1 mutations; stereotyped B-cell receptors; Survival Rate; Ubiquitin-Protein Ligases; Greece; Italy; Sweden; United Kingdom > UK; chronic lymphocytic leukemia; mutations; prognosis; immunoglobulin genes; stereotyped B-cell receptors
• ISSN: 0887-6924; 1476-5551; 1476-5551
• DOI: 10.1038/leu.2013.98

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.