Molecular Genetics of High-risk Chronic Lymphocytic Leukemia

Davide Rossi; Gianluca Gaidano


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

In This Article

Expert Commentary

Several uncovered aspects of high-risk molecular lesions in CLL remain to be clarified, including: the integration of NOTCH1, SF3B1 and BIRC3 mutations into the current prognostic algorithm based on cytogenetic abnormalities and TP53 mutations, the impact of NOTCH1, SF3B1 and BIRC3 mutations on response and PFS after treatment, the biological and functional consequence of NOTCH1, SF3B1 and BIRC3 mutations in CLL and the responsiveness of TP53, NOTCH1, SF3B1 and BIRC3 CLL mutants to novel CLL-targeted treatments.

The detection of recurrent chromosomal aberrations has been of extreme relevance for understanding the clinical heterogeneity of CLL.[19] Knowledge of the FISH karyotype at diagnosis has enabled the construction of a hierarchical model of cytogenetic lesions that correlates with outcome, and is commonly applied in the clinical practice for treatment tailoring, as exemplified by the case of 17p13 deletion.[19] Cytogenetic lesions identifiable by FISH; however, may not entirely explain the genetic basis of CLL clinical heterogeneity, as documented by the contribution of TP53 mutation assessment in identifying high-risk patients.[5,7,20–26] NOTCH1, SF3B1 and BIRC3 are among the first novel genes with prognostic relevance that have been identified through the application of whole genome/exome sequencing to CLL.[10–17] This finding prompts the integration of NOTCH1, SF3B1 and BIRC3 lesions into a comprehensive prognostic algorithm based on both chromosomal abnormalities and gene mutations.