Molecular Genetics of High-risk Chronic Lymphocytic Leukemia

Davide Rossi; Gianluca Gaidano

Disclosures

Expert Rev Hematol. 2012;5(6):593-602. 

In This Article

SF3B1 Mutations

Splicing of pre-mRNA and the formation of mature mRNA through the removal of introns in protein-encoding genes is carried out in the nucleus by the spliceosome, a complex of five small nuclear ribonucleoproteins (snRNPs).[50] These spliceosome components are required for normal constitutive and alternative splicing.[50] Alternative splicing can generate numerous transcript variants for each gene, thus adding to genomic complexity and potentially contributing to cancer, as suggested by the identification of a relationship between specific alterations in the splicing of oncogenes and tumor suppressors and tumor development.[51]

SF3B1 is a core component of the U2 snRNP that recognizes the 3' splice site at intron–exon junctions.[50,52–55] The SF3B1 protein interacts with RNA sequences in the vicinity of the branch point, as well as with the early 3'-splice-site recognition factor U2AF65 and the branch point-binding protein SF3B14.[50,52–55] Structurally, the SF3B1 protein has two well-defined regions: the N-terminal amino acid region that contains several protein-binding motifs and functions as a scaffold to facilitate its interaction with other splicing factors such as U2AF65 and SF3B14 and the C-terminal region that contains 22 nonidentical tandem repeats of the HEAT motif that meander around the SF3b complex, enclosing SF3B14.[50,52–55]

Whole genome/exome sequencing studies have revealed that SF3B1 is a recurrently mutated gene in CLL. SF3B1 mutations occur with a prevalence that ranges from 7 to 15% of CLL, depending on the composition of the CLL cohort and whether relapsed cases have been included in the case mix.[12–14]SF3B1 mutations in CLL are generally represented by missense nucleotide changes that cluster in selected HEAT repeats of the SF3B1 protein, and recurrently target three hotspots (codons 662, 666 and 700), with a single amino acid substitution (K700E) accounting for approximately 60% of all SF3B1 mutations.[12–14] Notably, an identical spectrum of SF3B1 mutations has also been identified in another hematopoietic tumor, namely myelodysplastic syndromes.[56,57]

At variance from NOTCH1 mutations, SF3B1 lesions do not seem to consistently cluster with any specific biological or cytogenetic subgroup of CLL.[12–14] Instead, SF3B1 mutations preferentially target specific aggressive phases of disease, since they are virtually absent in monoclonal B-cell lymphocytosis,[58] occur at a low rate at CLL presentation,[13] but are enriched in approximately 20% relapsed and chemorefractory CLL (Figures 1C & 2).[13] In Richter syndrome, SF3B1 mutations are virtually absent, thus reinforcing the notion that this disease is molecularly distinct from chemorefractory progression of CLL without transformation.[13,48] Consistent with the results of these analyses is the finding that newly diagnosed CLL patients harboring SF3B1 mutations are characterized by a short survival probability (~30–40% at 10 years).[12,13] Overall, these observations, along with a trend toward a mutually exclusive distribution of SF3B1 and TP53 abnormalities (Figure 2), prompt SF3B1 mutations as a potential novel biomarker for the early identification of high risk, but TP53 wild-type CLL patients.

The precise biological role of SF3B1 mutations in CLL is currently unknown. However, the clustering of SF3B1 mutations within structurally critical HEAT domains suggests that they are selected to modify SF3B1 interactions with other proteins of the SF3b complex, thus resulting in defective spliceosome assembly and deregulated normal and alternative mRNA splicing.[12–14]

In addition to pathogenetic and prognostic implications, SF3B1 mutations might also provide a therapeutic target for SF3B1 inhibitors, which are currently under preclinical development as anticancer drugs.[59]

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