Type 1 versus Type 2 calreticulin mutations in essential thrombocythemia: A collaborative study of 1027 patients

Ayalew Tefferi, Emnet A. Wassie, Paola Guglielmelli, Naseema Gangat, Alem A. Belachew, Terra L. Lasho, Christy Finke, Rhett P. Ketterling, Curtis A. Hanson, Animesh Pardanani, Alexandra P. Wolanskyj, Margherita Maffioli, Rosario Casalone, Annalisa Pacilli, Alessandro M. Vannucchi, Francesco Passamonti

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121 Scopus citations

Abstract

CALR (calreticulin) trails JAK2 as the second most mutated gene in essential thrombocythemia (ET). Mutant CALR in ET is a result of frameshift mutations, caused by exon 9 deletions or insertions; type-1, 52-bp deletion (p.L367fs*46), and type-2, 5-bp TTGTC insertion (p.K385fs*47) variants constitute more than 80% of these mutations. The current study includes a total of 1027 patients divided into test (n=402) and validation (n=625) cohorts. Among the 402 ET patients in the test cohort, 227 (57%) harbored JAK2, 11 (3%) Myeloproliferative leukemia virus oncogene (MPL), and 114 (28%) CALR mutations; 12% were wild-type for all three mutations (i.e., triple-negative). Among the 114 patients with CALR mutations, 51 (45%) displayed type-1 and 44 (39%) type-2 variants; compared to mutant JAK2, both variants were associated with higher platelet and lower hemoglobin and leukocyte counts. However, male sex was associated with only type-1 (P=0.005) and younger age with type-2 (P=0.001) variants. Notably, platelet count was significantly higher in type-2 vs. type-1 CALR-mutated patients (P=0.03) and the particular observation was validated in the validation cohort that included 111 CALR-mutated ET patients (P=0.002). These findings, coupled with the recent demonstration of preferential expression of mutant and wild-type CALR in megakaryocytes, suggest differential effects of CALR variants on thrombopoiesis. Am. J. Hematol. 89:E121-E124, 2014.

Original languageEnglish (US)
Pages (from-to)E121-E124
JournalAmerican journal of hematology
Volume89
Issue number8
DOIs
StatePublished - Aug 2014

ASJC Scopus subject areas

  • Hematology

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    Tefferi, A., Wassie, E. A., Guglielmelli, P., Gangat, N., Belachew, A. A., Lasho, T. L., Finke, C., Ketterling, R. P., Hanson, C. A., Pardanani, A., Wolanskyj, A. P., Maffioli, M., Casalone, R., Pacilli, A., Vannucchi, A. M., & Passamonti, F. (2014). Type 1 versus Type 2 calreticulin mutations in essential thrombocythemia: A collaborative study of 1027 patients. American journal of hematology, 89(8), E121-E124. https://doi.org/10.1002/ajh.23743