Abstract
Calreticulin (CALR) mutations were recently described in JAK2 and MPL unmutated primary myelofibrosis (PMF) and essential thrombocythemia. In the current study, we compared the clinical, cytogenetic and molecular features of patients with PMF with or without CALR, JAK2 or MPL mutations. Among 254 study patients, 147 (58%) harbored JAK2, 63 (25%) CALR and 21 (8.3%) MPL mutations; 22 (8.7%) patients were negative for all three mutations, whereas one patient expressed both JAK2 and CALR mutations. Study patients were also screened for ASXL1 (31%), EZH2 (6%), IDH (4%), SRSF2 (12%), SF3B1 (7%) and U2AF1 (16%) mutations. In univariate analysis, CALR mutations were associated with younger age (P<0.0001), higher platelet count (P<0.0001) and lower DIPSS-plus score (P=0.02). CALR-mutated patients were also less likely to be anemic, require transfusions or display leukocytosis. Spliceosome mutations were infrequent (P=0.0001) in CALR-mutated patients, but no other molecular or cytogenetic associations were evident. In multivariable analysis, CALR mutations had a favorable impact on survival that was independent of both DIPSS-plus risk and ASXL1 mutation status (P=0.001; HR 3.4 for triple-negative and 2.2 for JAK2-mutated). Triple-negative patients also displayed inferior LFS (P=0.003). The current study identifies ‘CALR–ASXL1+’ and ‘triple-negative’ as high-risk molecular signatures in PMF.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Eggleton P, Michalak M . Calreticulin for better or for worse, in sickness and in health, until death do us part. Cell Calcium 2013; 54: 126–131.
Nakamura K, Robertson M, Liu G, Dickie P, Guo JQ, Duff HJ et al. Complete heart block and sudden death in mice overexpressing calreticulin. J Clin Invest 2001; 107: 1245–1253.
Mesaeli N, Nakamura K, Zvaritch E, Dickie P, Dziak E, Krause KH et al. Calreticulin is essential for cardiac development. J Cell Biol 1999; 144: 857–868.
Raghavan M, Wijeyesakere SJ, Peters LR, Del Cid N . Calreticulin in the immune system: ins and outs. Trends Immunol 2013; 34: 13–21.
Lee D, Oka T, Hunter B, Robinson A, Papp S, Nakamura K et al. Calreticulin induces dilated cardiomyopathy. PLoS One 2013; 8: e56387.
Wang WA, Groenendyk J, Michalak M . Calreticulin signaling in health and disease. Int J Biochem Cell Biol 2012; 44: 842–846.
Wemeau M, Kepp O, Tesniere A, Panaretakis T, Flament C, De Botton S et al. Calreticulin exposure on malignant blasts predicts a cellular anticancer immune response in patients with acute myeloid leukemia. Cell Death Dis 2010; 1: e104.
Gold LI, Eggleton P, Sweetwyne MT, Van Duyn LB, Greives MR, Naylor SM et al. Calreticulin: non-endoplasmic reticulum functions in physiology and disease. FASEB J 2010; 24: 665–683.
Papp S, Dziak E, Opas M . Embryonic stem cell-derived cardiomyogenesis: a novel role for calreticulin as a regulator. Stem Cells 2009; 27: 1507–1515.
Panaretakis T, Kepp O, Brockmeier U, Tesniere A, Bjorklund AC, Chapman DC et al. Mechanisms of pre-apoptotic calreticulin exposure in immunogenic cell death. EMBO J 2009; 28: 578–590.
Michalak M, Groenendyk J, Szabo E, Gold LI, Opas M . Calreticulin, a multi-process calcium-buffering chaperone of the endoplasmic reticulum. Biochem J 2009; 417: 651–666.
Obeid M, Tesniere A, Ghiringhelli F, Fimia GM, Apetoh L, Perfettini JL et al. Calreticulin exposure dictates the immunogenicity of cancer cell death. Nat Med 2007; 13: 54–61.
Coppolino MG, Woodside MJ, Demaurex N, Grinstein S, St-Arnaud R, Dedhar S . Calreticulin is essential for integrin-mediated calcium signalling and cell adhesion. Nature 1997; 386: 843–847.
Vaksman O, Davidson B, Trope C, Reich R . Calreticulin expression is reduced in high-grade ovarian serous carcinoma effusions compared with primary tumors and solid metastases. Human Pathol 2013; 44: 2677–2683.
Sheng W, Chen C, Dong M, Zhou J, Liu Q, Dong Q et al. Overexpression of calreticulin contributes to the development and progression of pancreatic cancer. J Cell Physiol 2013; e-pub ahead of print 22 November 2013; doi:10.1002/jcp.24519.
Eric-Nikolic A, Milovanovic Z, Sanchez D, Pekarikova A, Dzodic R, Matic IZ et al. Overexpression of calreticulin in malignant and benign breast tumors: relationship with humoral immunity. Oncology 2012; 82: 48–55.
Aghajani A, Rahimi A, Fadai F, Ebrahimi A, Najmabadi H, Ohadi M . A point mutation at the calreticulin gene core promoter conserved sequence in a case of schizophrenia. Am J Med Genet B Neuropsychiatr Genet 2006; 141B: 294–295.
Nangalia J, Massie CE, Baxter EJ, Nice FL, Gundem G, Wedge DC et al. Somatic CALR mutations in myeloproliferative neoplasms with nonmutated JAK2. New Engl J Med 2013; 369: 2391–2405.
Klampfl T, Gisslinger H, Harutyunyan AS, Nivarthi H, Rumi E, Milosevic JD et al. Somatic mutations of calreticulin in myeloproliferative neoplasms. New Engl J Med 2013; 369: 2379–2390.
Vardiman JW, Thiele J, Arber DA, Brunning RD, Borowitz MJ, Porwit A et al. The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes. Blood 2009; 114: 937–951.
Caramazza D, Begna KH, Gangat N, Vaidya R, Siragusa S, Van Dyke DL et al. Refined cytogenetic-risk categorization for overall and leukemia-free survival in primary myelofibrosis: a single center study of 433 patients. Leukemia 2011; 25: 82–88.
Gangat N, Caramazza D, Vaidya R, George G, Begna K, Schwager S et al. DIPSS plus: a refined Dynamic International Prognostic Scoring System for primary myelofibrosis that incorporates prognostic information from karyotype, platelet count, and transfusion status. J Clin Oncol 2011; 29: 392–397.
Patnaik MM, Padron E, LaBorde RR, Lasho TL, Finke CM, Hanson CA et al. Mayo prognostic model for WHO-defined chronic myelomonocytic leukemia: ASXL1 and spliceosome component mutations and outcomes. Leukemia 2013; 27: 1504–1510.
Patnaik MM, Lasho TL, Finke CM, Hanson CA, Hodnefield JM, Knudson RA et al. Spliceosome mutations involving SRSF2, SF3B1, and U2AF35 in chronic myelomonocytic leukemia: prevalence, clinical correlates, and prognostic relevance. Am J Hematol 2013; 88: 201–206.
Tefferi A, Finke CM, Lasho TL, Wassie EA, Knudson R, Ketterling RP et al. U2AF1 mutations in primary myelofibrosis are strongly associated with anemia and thrombocytopenia despite clustering with JAK2V617F and normal karyotype. Leukemia 2013; e-pub ahead of print 7 October 2013; doi:10.1038/leu.2013.286.
Lasho TL, Jimma T, Finke CM, Patnaik M, Hanson CA, Ketterling RP et al. SRSF2 mutations in primary myelofibrosis: significant clustering with IDH mutations and independent association with inferior overall and leukemia-free survival. Blood 2012; 120: 4168–4171.
Tefferi A, Jimma T, Sulai NH, Lasho TL, Finke CM, Knudson RA et al. IDH mutations in primary myelofibrosis predict leukemic transformation and shortened survival: clinical evidence for leukemogenic collaboration with JAK2V617F. Leukemia 2012; 26: 475–480.
Lasho TL, Finke CM, Hanson CA, Jimma T, Knudson RA, Ketterling RP et al. SF3B1 mutations in primary myelofibrosis: clinical, histopathology and genetic correlates among 155 patients. Leukemia 2012; 26: 1135–1137.
Vannucchi AM, Lasho TL, Guglielmelli P, Biamonte F, Pardanani A, Pereira A et al. Mutations and prognosis in primary myelofibrosis. Leukemia 2013; 27: 1861–1869.
Guglielmelli P, Biamonte F, Score J, Hidalgo-Curtis C, Cervantes F, Maffioli M et al. EZH2 mutational status predicts poor survival in myelofibrosis. Blood 2011; 118: 5227–5234.
Vaidya R, Caramazza D, Begna KH, Gangat N, Van Dyke DL, Hanson CA et al. Monosomal karyotype in primary myelofibrosis is detrimental to both overall and leukemia-free survival. Blood 2011; 117: 5612–5615.
Tefferi A, Pardanani A, Gangat N, Begna KH, Hanson CA, Van Dyke DL et al. Leukemia risk models in primary myelofibrosis: an International Working Group study. Leukemia 2012; 26: 1439–1441.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no conflict of interest.
Rights and permissions
About this article
Cite this article
Tefferi, A., Lasho, T., Finke, C. et al. CALR vs JAK2 vs MPL-mutated or triple-negative myelofibrosis: clinical, cytogenetic and molecular comparisons. Leukemia 28, 1472–1477 (2014). https://doi.org/10.1038/leu.2014.3
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/leu.2014.3
Keywords
This article is cited by
-
STAT5a and SH2B3 novel mutations display malignancy roles in a triple-negative primary myelofibrosis patient
Cancer Gene Therapy (2024)
-
Systemic inflammatory indices for predicting prognosis of myelofibrosis
Scientific Reports (2023)
-
Allelic burden of Janus kinase 2 in a 6-month course of therapy for myeloproliferative neoplasms
Molecular Biology Reports (2023)
-
Digital-droplet PCR assays for IDH, DNMT3A and driver mutations to monitor after allogeneic stem cell transplantation minimal residual disease of myelofibrosis
Bone Marrow Transplantation (2022)
-
Mutations in the miR-142 gene are not common in myeloproliferative neoplasms
Scientific Reports (2022)