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

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

Subjects

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

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Subscribe to this journal

Receive 12 print issues and online access

$259.00 per year

only $21.58 per issue

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Additional access options:

Figure 1

References

  1. Dohner H, Stilgenbauer S, Benner A, Leupolt E, Krober A, Bullinger L et al. Genomic aberrations and survival in chronic lymphocytic leukemia. N Engl J Med 2000; 343: 1910–1916.
    Article CAS PubMed Google Scholar
  2. Gunnarsson R, Isaksson A, Mansouri M, Goransson H, Jansson M, Cahill N et al. Large but not small copy-number alterations correlate to high-risk genomic aberrations and survival in chronic lymphocytic leukemia: a high-resolution genomic screening of newly diagnosed patients. Leukemia 2010; 24: 211–215.
    Article CAS PubMed Google Scholar
  3. Zenz T, Eichhorst B, Busch R, Denzel T, Habe S, Winkler D et al. TP53 mutation and survival in chronic lymphocytic leukemia. J Clin Oncol 2010; 28: 4473–4479.
    Article PubMed Google Scholar
  4. Fabbri G, Rasi S, Rossi D, Trifonov V, Khiabanian H, Ma J et al. Analysis of the chronic lymphocytic leukemia coding genome: role of NOTCH1 mutational activation. J Exp Med 2011; 208: 1389–1401.
    Article CAS PubMed PubMed Central Google Scholar
  5. Puente XS, Pinyol M, Quesada V, Conde L, Ordonez GR, Villamor N et al. Whole-genome sequencing identifies recurrent mutations in chronic lymphocytic leukaemia. Nature 2011; 475: 101–105.
    Article CAS PubMed PubMed Central Google Scholar
  6. Rossi D, Bruscaggin A, Spina V, Rasi S, Khiabanian H, Messina M et al. Mutations of the SF3B1 splicing factor in chronic lymphocytic leukemia: association with progression and fludarabine-refractoriness. Blood 2011; 118: 6904–6908.
    Article CAS PubMed PubMed Central Google Scholar
  7. Wang L, Lawrence MS, Wan Y, Stojanov P, Sougnez C, Stevenson K et al. SF3B1 and other novel cancer genes in chronic lymphocytic leukemia. N Engl J Med 2011; 365: 2497–2506.
    Article CAS PubMed PubMed Central Google Scholar
  8. Quesada V, Conde L, Villamor N, Ordonez GR, Jares P, Bassaganyas L et al. Exome sequencing identifies recurrent mutations of the splicing factor SF3B1 gene in chronic lymphocytic leukemia. Nat Genet 2012; 44: 47–52.
    Article CAS Google Scholar
  9. Rossi D, Fangazio M, Rasi S, Vaisitti T, Monti S, Cresta S et al. Disruption of BIRC3 associates with fludarabine chemorefractoriness in TP53 wild-type chronic lymphocytic leukemia. Blood 2012; 119: 2854–2862.
    Article CAS PubMed Google Scholar
  10. Rossi D, Rasi S, Fabbri G, Spina V, Fangazio M, Forconi F et al. Mutations of NOTCH1 are an independent predictor of survival in chronic lymphocytic leukemia. Blood 2012; 119: 521–529.
    Article CAS PubMed PubMed Central Google Scholar
  11. Balatti V, Lerner S, Rizzotto L, Rassenti LZ, Bottoni A, Palamarchuk A et al. Trisomy 12 CLLs progress through NOTCH1 mutations. Leukemia 2012; e-pub ahead of print 20 August 2012; doi: 10.1038/leu.2012.239.
    Article PubMed PubMed Central Google Scholar
  12. Del Giudice I, Rossi D, Chiaretti S, Marinelli M, Tavolaro S, Gabrielli S et al. NOTCH1 mutations in +12 chronic lymphocytic leukemia (CLL) confer an unfavorable prognosis, induce a distinctive transcriptional profiling and refine the intermediate prognosis of +12 CLL. Haematologica 2012; 97: 437–441.
    Article CAS PubMed PubMed Central Google Scholar
  13. Lopez C, Delgado J, Costa D, Conde L, Ghita G, Villamor N et al. Different distribution of NOTCH1 mutations in chronic lymphocytic leukemia with isolated trisomy 12 or associated with other chromosomal alterations. Genes Chromosomes Cancer 2012; 51: 881–889.
    Article CAS PubMed Google Scholar
  14. Zainuddin N, Murray F, Kanduri M, Gunnarsson R, Smedby KE, Enblad G et al. TP53 Mutations are infrequent in newly diagnosed chronic lymphocytic leukemia. Leuk Res 2011; 35: 272–274.
    Article CAS PubMed Google Scholar
  15. Smedby KE, Hjalgrim H, Melbye M, Torrang A, Rostgaard K, Munksgaard L et al. Ultraviolet radiation exposure and risk of malignant lymphomas. J Natl Cancer Inst 2005; 97: 199–209.
    Article PubMed Google Scholar

Download references

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.

Author information

Author notes

  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

Authors

  1. L Mansouri
    You can also search for this author inPubMed Google Scholar
  2. N Cahill
    You can also search for this author inPubMed Google Scholar
  3. K E Smedby
    You can also search for this author inPubMed Google Scholar
  4. E Tjönnfjord
    You can also search for this author inPubMed Google Scholar
  5. H Hjalgrim
    You can also search for this author inPubMed Google Scholar
  6. G Juliusson
    You can also search for this author inPubMed Google Scholar
  7. C Geisler
    You can also search for this author inPubMed Google Scholar
  8. R Rosenquist
    You can also search for this author inPubMed Google Scholar

Corresponding author

Correspondence toR Rosenquist.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

About this article

Cite this article

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

Download citation

This article is cited by