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Differential association of calreticulin type 1 and type 2 mutations with myelofibrosis and essential thrombocytemia: relevance for disease evolution

Leukemia volume 29, pages 249–252 (2015)Cite this article

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Recent advances in myeloproliferative neoplasms (MPNs) have highlighted the prevalence of mutations in the calreticulin gene (CALR),1,2 bringing a major new actor in these disorders. Numerous studies have highly contributed to understanding of the role of JAK2 and MPL in the pathogenesis of MPN development and progression.3, 4, 5 In contrast to JAK2 mutations that are associated in a causative manner with polycythemia vera,6 myelofibrosis (MF) or essential thrombocytemia (ET),7 CALR mutations are only associated with ET and MF. Indeed, CALR mutations were reported in 25% of ET and in 35% of MF patients who were non-mutated for JAK2 and MPL. All recurrent CALR mutations that have been observed lead to a frame-shift generating a common 36 amino-acid C-terminal end and loss of the KDEL motif.1,2,8, 9, 10, 11 Among these mutations, two variants are largely predominant: type 1, a 52-bp deletion (p.L367fs*46) and type 2, a 5-bp insertion (p.K385fs*47). They account for 85% of the CALR mutations in ET and primary myelofibrosis (PMF).1,2 There is strong evidence that the clinical features of CALR and JAK2-mutated ET and PMF are different and represent two facets of these disorders, although they both activate the JAK/STAT signaling pathway. It remains possible that the different CALR mutants exert different signaling activities. Thus, it would be important to characterize the potential differences between the different CALR mutations and also the phenotype of MPN devoid of JAK2, MPL and CALR mutations, now called triple-negative MPNs to understand whether they represent a homogeneous population.

A total of 572 MPN patients negative for JAK2 and MPL mutations were collected according to sex, age at diagnosis and main clinical characteristics from several French and Belgian hospitals under the auspices of French Intergroup of Myeloproliferative disorders. The mutational status of CALR was determined using previously described high-resolution sizing of fluorescent dye-labeled PCR amplification of exon 9, with Sanger sequencing controls.1 Beyond its contribution to mutant detection, high-resolution sizing also allows to estimate the allelic burden. Laboratory data and clinical parameters were obtained at diagnosis. The GraphPad Prism statistical package (GraphPad Software, Inc., La Jolla, CA, USA) was used to perform statistical analysis on these data, as described in Supplementary Information.

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Acknowledgements

We thank F Fava, C Legrand, I Teyssandier, F Lorre, R Tang and Laboratoire Commun de Biologie et Génétique Moléculaires, AP-HP, hôpital Saint-Antoine, Drs D Carp, J Dewulf, S Frederic, L Heuberger, I Leduc, F Lefrere, E Legac, E Ronez, J Roussi, C Salanoubat, J-L Vaerman, M Van Butsel, MD Venon, Professor D Latinne and Professor O Legrand for molecular and clinical biology support. This work was supported by grants from la Ligue contre le Cancer (XC, IP, ES WV and OB, équipe labellisée 2012), from the Agence Nationale de la Recherche (IP, WV ANR Thrombocytosis and GERMPN) and the Laurette Fugain association (WV). XC and OB are supported respectively by grants from the University Paris Diderot and from the ANR. We are grateful for generous support to S.N.C. from the F.R.S.-F.N.R.S., Belgium, the Salus Sanguinis Foundation, the Action de Recherche Concertée ARC10/15-027, the Fondation contre le Cancer, Brussels, and the PAI Program Belgian Medical Genetics Initiative Project P7/43 (BeMG) IAP, Belgium.

Author information

Author notes

  1. C Marzac and O Bluteau: These authors contributed equally to this work.

Authors and Affiliations

  1. UMR 1009 INSERM, Laboratory of Excellence GR-Ex, Villejuif, France

    X Cabagnols, F Pasquier, V Ribrag, E Solary, I Plo, N Casadevall, W Vainchenker & O Bluteau

  2. Gustave Roussy, UMR 1009, Villejuif, France

    X Cabagnols, F Pasquier, V Ribrag, E Solary, I Plo, N Casadevall, W Vainchenker & O Bluteau

  3. Université Paris-Sud, UMR 1009, Villejuif, France

    X Cabagnols, F Pasquier, V Ribrag, E Solary, I Plo, W Vainchenker & O Bluteau

  4. Ludwig Institute for Cancer Research, Brussels, Belgium

    J P Defour & S N Constantinescu

  5. de Duve Institute, Université catholique de Louvain, Brussels, Belgium

    J P Defour, L Knoops & S N Constantinescu

  6. Department of Clinical Biology, Cliniques universitaires St Luc, Brussels, Belgium

    J P Defour & P Saussoy

  7. CHU de Brest, Laboratoire d'Hématologie, Brest, France

    V Ugo & J C Ianotto

  8. Université de Brest, Faculté de Médecine, Université Européenne de Bretagne, Brest, France

    V Ugo

  9. INSERM U1078, Brest, France

    V Ugo

  10. UMR 5525 CNRS- équipe TheRex, Université Joseph Fourier- Grenoble-1 Grenoble, France

    P Mossuz & J Mondet

  11. Laboratoire d'Hématologie, CHU de Dijon, Dijon, France

    F Girodon & J H Alexandre

  12. INSERM U866, Faculté de Médecine, Dijon, France

    F Girodon

  13. Laboratoire d'Hématologie, CHU de Bordeaux et Laboratoire Hématopoïèse Leucémique et Cibles Thérapeutiques, INSERM U1035, Université de Bordeaux, Bordeaux, France

    O Mansier & E Lippert

  14. Service de Médecine Interne et Maladies Infectieuses, Hôpital Haut-Lévêque, CHU de Bordeaux, Bordeaux, France

    J F Viallard

  15. Département de Biopathologie et d’Oncologie Moléculaire, Institut Paoli-Calmettes, Marseille, France

    A Murati & M J Mozziconacci

  16. Department of Hematology, Cliniques universitaires St Luc, Brussels, Belgium

    M C Vekemans

  17. AP-HP, Hôpital Saint-Antoine, Laboratoire d’Hématologie, Paris, France

    N Casadevall & C Marzac

  18. Sorbonne Universités, UPMC Univ Paris 06, GRC n°07, Groupe de Recherche Clinique sur les Myéloproliférations Aiguës et Chroniques MyPAC, Paris, France

    C Marzac

  19. INSERM, UMR_S 938, CDR Saint-Antoine, Paris, France

    C Marzac

Authors
  1. X Cabagnols
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  2. J P Defour
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Corresponding author

Correspondence to C Marzac.

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Cabagnols, X., Defour, J., Ugo, V. et al. Differential association of calreticulin type 1 and type 2 mutations with myelofibrosis and essential thrombocytemia: relevance for disease evolution. Leukemia 29, 249–252 (2015). https://doi.org/10.1038/leu.2014.270

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