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Type 1 vs type 2 calreticulin mutations in primary myelofibrosis: differences in phenotype and prognostic impact

Leukemia volume 28, pages 1568–1570 (2014)Cite this article

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Calreticulin (CALR) is a multifunctional Ca2+-binding protein located in the endoplasmic reticulum. CALR mutations are recurrent in JAK2/MPL-unmutated essential thrombocythemia (ET) and primary myelofibrosis (PMF), with reported mutational frequencies of 49 and 74%, respectively.1, 2 CALR mutations seen in ET and PMF are exon 9 frameshift mutations that result from somatic insertions, deletions or complex insertion/deletions.3, 4 However, more than 80% of mutated patients harbor one of only two mutation variants: type 1, a 52-bp deletion (p.L367fs*46) and type 2, a 5-bp TTGTC insertion (p.K385fs*47).3 In a recent World Health Organization-defined ET report,2 deletions (type 1 being the commonest) constituted 61% of the CALR mutations and insertions (type 2 being the commonest) the remaining. In another large ET study,5 the respective frequencies of type 1 and type 2 CALR mutations were 46 and 38%. In PMF, type 1 and type 2 variants were reported in ∼69 and 21% of all CALR-mutated cases, respectively.3

CALR mutations in ET were shown to correlate with male sex, younger age, lower leukocyte count, lower hemoglobin level and higher platelet count2 and in PMF with younger age, higher platelet count and lower incidences of anemia, leukocytosis and spliceosome mutations.1 In addition, CALR mutations in ET were associated with longer thrombosis-free survival2, 5 and in PMF with longer overall survival.1 Prognosis in CALR-mutated PMF is further modified by the presence (unfavorable) or absence (favorable) of ASXL1 mutations.1 The latter was previously shown to predict poor survival in PMF,6 independent of the dynamic international prognostic scoring system (DIPSS)-plus7 or IPSS.8 In the current study, we examined the possibility that type 1 (p.L367fs*46) and type 2 (p.K385fs*47) CALR mutations differ in their phenotype and prognostic impact.

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References

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Authors and Affiliations

  1. Division of Hematology, Mayo Clinic, Rochester, MN, USA

    A Tefferi, T L Lasho, C Finke, A A Belachew, E A Wassie & A Pardanani

  2. Division of Cytogenetics, Mayo Clinic, Rochester, MN, USA

    R P Ketterling

  3. Division of Hematopathology, Mayo Clinic, Rochester, MN, USA

    C A Hanson

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  1. A Tefferi
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  2. T L Lasho
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  7. C A Hanson
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  8. A Pardanani
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Correspondence to A Tefferi.

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Tefferi, A., Lasho, T., Finke, C. et al. Type 1 vs type 2 calreticulin mutations in primary myelofibrosis: differences in phenotype and prognostic impact. Leukemia 28, 1568–1570 (2014). https://doi.org/10.1038/leu.2014.83

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