Calreticulin (CALR) mutations were recently identified in patients with essential thrombocythemia (ET) and primary myelofibrosis (PMF) devoid of JAK2 and MPL mutations. We evaluated the clinical, laboratory, and molecular features of a Taiwanese population of patients with ET. Among 147 ET patients, CALR mutations were detected in 33 (22.5 %), JAK2V617F in 94 (63.9 %), and MPL mutations in 4 (2.7 %). Sixteen (10.9 %) patients were negative for all three mutations (CALR, JAK2V617F, and MPL; triple negative). Interestingly, one patient with the type 2 CALR mutation also harbored a low allele burden (0.025 %) of JAK2V617F mutation. Furthermore, we found a novel CALR mutation, with the resultant protein sharing an identical amino acid sequence to the type 6 CALR mutant. Compared to those with JAK2 mutation, CALR-mutated ET patients were characterized by younger age, lower leukocyte count, higher platelet count, and decreased risk of thrombosis. CARL mutations had a favorable impact on thrombosis-free survival (TFS) for ET patients, whereas the respective TFS outcomes were similarly poorer in JAK2-mutated ET and PV patients. Multivariate analysis confirmed that younger age (<60 years), presence of CALR mutations, and a lower platelet count (<1,000 × 109/L) were independently associated with a longer TFS in ET patients. The current study demonstrates that CALR mutations characterize a special group of ET patients with unique phenotypes that are not discrepant from those seen in Western countries.
The study was supported by the National Science Council grant to CC Chen (NSC102-2314-B-182-047), Chang-Gung Memorial Hospital grants to CC Chen (CMRPG6B0221 and CMRPG6B0371), and Taipei Veterans General Hospital grant to JP Gau (VGH102C-202).
Conflict of interest
All authors declare that there are no competing financial interests in relation to the work.
Tefferi A, Vardiman JW (2008) Classification and diagnosis of myeloproliferative neoplasms: the 2008 World Health Organization criteria and point-of-care diagnostic algorithms. Leukemia 22:14–22PubMedCrossRefGoogle Scholar
Klampfl T, Gisslinger H, Harutyunyan AS et al (2013) Somatic mutations of calreticulin in myeloproliferative neoplasms. N Engl J Med 369:2379–2390PubMedCrossRefGoogle Scholar
Rumi E, Pietra D, Ferretti V et al (2014) JAK2 or CALR mutation status defines subtypes of essential thrombocythemia with substantially different clinical course and outcomes. Blood 123:1544–1551PubMedCentralPubMedCrossRefGoogle Scholar
Rotunno G, Mannarelli C, Guglielmelli P et al (2014) Impact of calreticulin mutations on clinical and hematological phenotype and outcome in essential thrombocythemia. Blood 123:1552–1555PubMedCrossRefGoogle Scholar
Swerdlow SHCE, Harris NL et al (2008) WHO classification of tumours of haematopoietic and lymphoid tissues. International Agency for Research on Cancer, LyonGoogle Scholar
Barosi G, Mesa RA, Thiele J et al (2008) Proposed criteria for the diagnosis of post-polycythemia vera and post-essential thrombocythemia myelofibrosis: a consensus statement from the International Working Group for Myelofibrosis Research and Treatment. Leukemia 22:437–438PubMedCrossRefGoogle Scholar
Barbui T, Barosi G, Birgegard G et al (2011) Philadelphia-negative classical myeloproliferative neoplasms: critical concepts and management recommendations from European LeukemiaNet. J Clin Oncol 29:761–770PubMedCrossRefGoogle Scholar
Vannucchi AM, Antonioli E, Guglielmelli P et al (2007) Clinical profile of homozygous JAK2 617V>F mutation in patients with polycythemia vera or essential thrombocythemia. Blood 110:840–846PubMedCrossRefGoogle Scholar
Bench AJ, White HE, Foroni L et al (2013) Molecular diagnosis of the myeloproliferative neoplasms: UK guidelines for the detection of JAK2 V617F and other relevant mutations. Br J Haematol 160:25–34PubMedCrossRefGoogle Scholar
Kroger N, Badbaran A, Holler E et al (2007) Monitoring of the JAK2-V617F mutation by highly sensitive quantitative real-time PCR after allogeneic stem cell transplantation in patients with myelofibrosis. Blood 109:1316–1321PubMedCrossRefGoogle Scholar
Beer PA, Campbell PJ, Scott LM et al (2008) MPL mutations in myeloproliferative disorders: analysis of the PT-1 cohort. Blood 112:141–149PubMedCrossRefGoogle Scholar
Chaligne R, Tonetti C, Besancenot R et al (2008) New mutations of MPL in primitive myelofibrosis: only the MPL W515 mutations promote a G1/S-phase transition. Leukemia 22:1557–1566PubMedCrossRefGoogle Scholar
Pecquet C, Staerk J, Chaligne R et al (2010) Induction of myeloproliferative disorder and myelofibrosis by thrombopoietin receptor W515 mutants is mediated by cytosolic tyrosine 112 of the receptor. Blood 115:1037–1048PubMedCrossRefGoogle Scholar
Rumi E, Pietra D, Guglielmelli P et al (2013) Acquired copy-neutral loss of heterozygosity of chromosome 1p as a molecular event associated with marrow fibrosis in MPL-mutated myeloproliferative neoplasms. Blood 121:4388–4395PubMedCentralPubMedCrossRefGoogle Scholar
Martinez-Aviles L, Alvarez-Larran A, Besses C et al (2012) Clinical significance of clonality assessment in JAK2V617F-negative essential thrombocythemia. Ann Hematol 91:1555–1562PubMedCrossRefGoogle Scholar
Passamonti F, Thiele J, Girodon F et al (2012) A prognostic model to predict survival in 867 World Health Organization-defined essential thrombocythemia at diagnosis: a study by the International Working Group on Myelofibrosis Research and Treatment. Blood 120:1197–1201PubMedCrossRefGoogle Scholar
Barbui T, Finazzi G, Carobbio A et al (2012) Development and validation of an International Prognostic Score of thrombosis in World Health Organization-essential thrombocythemia (IPSET-thrombosis). Blood 120:5128–5133, quiz 5252PubMedCrossRefGoogle Scholar
Carobbio A, Thiele J, Passamonti F et al (2011) Risk factors for arterial and venous thrombosis in WHO-defined essential thrombocythemia: an international study of 891 patients. Blood 117:5857–5859PubMedCrossRefGoogle Scholar
Tefferi A, Lasho TL, Finke CM et al (2014) CALR vs JAK2 vs MPL-mutated or triple-negative myelofibrosis: clinical, cytogenetic and molecular comparisons. Leukemia. doi:10.1038/leu.2014.3
Tefferi A, Wassie EA, Guglielmelli P et al (2014) Type 1 vs Type 2 calreticulin mutations in essential thrombocythemia: a collaborative study of 1027 patients. Am J Hematol doi:10.1002/ajh.23743