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NOTCH1 and SF3B1 mutations can be added to the hierarchical prognostic classification in chronic lymphocytic leukemia

Leukemia volume 27, pages 512–514 (2013)Cite this article

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During recent years, a variety of novel molecular markers have been proposed as prognostic factors in chronic lymphocytic leukemia (CLL), which has significantly improved the subdivision of the disease. One of the strongest markers is fluorescence in situ hybridization detection of certain genomic aberrations, that is, del(11q), trisomy 12, del(13q) and del(17p), which is now included in routine diagnostics to guide decisions about therapy.1 More specifically, CLL patients with the 13q deletion (as a single aberration) have a more indolent disease course, whereas patients with 11q or, in particular, 17p deletions experience a more rapid disease progression with need of early treatment, and a generally poor overall survival.1, 2 Notably, CLL patients with 17p deletions and/or TP53 mutations belong to the category of patients with the worst outcome in CLL, as they generally do not respond to the current state-of-the-art treatment with fludarabine, cyclophosphamide and rituximab.1, 3

More recently, the advent of next-generation sequencing has revealed a number of novel genes to be frequently mutated in CLL, such as NOTCH1, SF3B1, BIRC3 and MYD88.4, 5, 6, 7, 8, 9, 10 In the pivotal studies, NOTCH1 mutations were identified in up to 12% of patients, and the mutations were strongly associated with progressive disease, treatment resistance, increased risk for Richter transformation and poor overall survival.4, 5, 10 Furthermore, it has also been observed that trisomy 12 patients have a high frequency of NOTCH1 mutations (up to 50%), and that CLL patients with concurrent trisomy 12 and NOTCH1 alterations display a particularly poor prognosis.11, 12, 13 Interestingly, the majority of cases with the NOTCH1 lesions show a recurrent dinucleotide hotspot deletion within the NOTCH1 PEST domain within exon 34. From in vitro studies, it appears that the mutated protein leads to upregulation of the NOTCH1 signaling pathway, resulting in an increased CLL cell survival and resistance to apoptosis.5

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Acknowledgements

This research was supported by the Nordic Cancer Union, the Swedish Cancer Society, the Swedish Research Council and the Lion’s Cancer Research Foundation, Uppsala.

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  1. L Mansouri and N Cahill: These authors contributed equally to this work

Authors and Affiliations

  1. Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden

    L Mansouri, N Cahill, R Gunnarsson & R Rosenquist

  2. Department of Medicine, Clinical Epidemiology Unit, Karolinska Institutet, Stockholm, Sweden

    K E Smedby

  3. Department of Hematology, Leukemia Laboratory, Rigshospitalet, Copenhagen, Denmark

    E Tjönnfjord & C Geisler

  4. Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark

    H Hjalgrim

  5. Department of Laboratory Medicine, Stem Cell Center, Hematology and Transplantation, Lund University, Lund, Sweden

    G Juliusson

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Correspondence to R Rosenquist.

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Mansouri, L., Cahill, N., Gunnarsson, R. et al. NOTCH1 and SF3B1 mutations can be added to the hierarchical prognostic classification in chronic lymphocytic leukemia. Leukemia 27, 512–514 (2013). https://doi.org/10.1038/leu.2012.307

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