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Looking for CALR mutations in familial myeloproliferative neoplasms

Leukemia volume 28, pages 1357–1360 (2014)Cite this article

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Diseases commonly referred to as chronic myeloproliferative neoplasms (MPNs) comprise essential thrombocythemia (ET), polycythemia vera (PV), primary myelofibrosis (PMF) and chronic myeloid leukemia (CML), and are acquired, clonal disorders arising at the stem-cell level characterized by overproduction of terminally differentiated myeloid cells and a variable propensity to transform into acute leukemia.1 Although the underlying genetic defect in CML has been known for different decades, the genetic complexity of Philadelphia-negative MPNs has only more recently been unraveled. The somatic gain-of-function mutation JAK2V617F has been described in the vast majority of patients with PV and in 50–60% of those with ET and PMF.2 Subsequently, several additional mutations have been reported in a fraction of MPN patients (that is, mutations in JAK2 exon 12, MPL, CBL, TET2, DNMT3A, IDH1/2, EZH2 and ASXL1, among others).3, 4, 5, 6, 7 Very recently, two seminal publications reported on new mutations in the CALR gene in a substantial proportion of sporadic ET and PMF patients lacking the JAK2V617F mutation.8, 9

Even though the majority of MPN cases described appears to be sporadic, the existence of familial MPNs (that is, pedigrees in which at least two members have an MPN) is well known.10, 11, 12 The reported prevalence of familial cases within a population of MPN patients is ∼7.6–11.0% and might even be underestimated.11, 13 A large Swedish population-based study has identified an approximately five to sevenfold increased relative risk of developing an MPN in first-degree relatives of affected patients.10 Familial MPN patients may harbor somatically acquired JAK2, MPL and TET2 mutations, and different MPN phenotypes and genotypes may coexist within a pedigree without a specific segregation pattern.13, 14 Patients seem to inherit a hitherto scarcely characterized ‘predisposition’ to develop MPN-related mutations. Patterns of inheritance are heterogeneous and disease anticipation between generations has been described.

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Acknowledgements

Research reported in this publication was supported by the AIL (Associazione Italiana Leucemie) Onlus Varese.

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Authors and Affiliations

  1. Division of Hematology, Department of Medicine, University Hospital Ospedale di Circolo e Fondazione Macchi, Varese, Italy

    M Maffioli, D Caramazza, B Mora, M Merli & F Passamonti

  2. Genetic Unit, Medical Genetic and Cytogenetics Laboratory, SSD, SMEL, University Hospital Ospedale di Circolo e Fondazione Macchi, Varese, Italy

    A Genoni, A Bussini & R Casalone

  3. Institute of Biomedical Engineering, National Research Council of Italy (ISIB-CNR), Padua, Italy

    T Giorgino

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  1. M Maffioli
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  2. A Genoni
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  3. D Caramazza
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  8. R Casalone
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  9. F Passamonti
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Correspondence to F Passamonti.

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The authors declare no conflict of interest.

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Author contributions

MMa and FP designed the study, analyzed and interpreted the data, and wrote the paper; AG, AB and RC performed CALR and JAK2 analyses; DC and BM analyzed and interpreted the data; MMe contributed to clinical data; TG performed statistical analysis. All authors drafted and approved the manuscript.

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Maffioli, M., Genoni, A., Caramazza, D. et al. Looking for CALR mutations in familial myeloproliferative neoplasms. Leukemia 28, 1357–1360 (2014). https://doi.org/10.1038/leu.2014.33

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