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Prognostic effect of calreticulin mutations in patients with myelofibrosis after allogeneic hematopoietic stem cell transplantation

Leukemia volume 28, pages 1552–1555 (2014)Cite this article

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Recently, somatic frameshift mutations in exon 9 of calreticulin (CALR) have been identified in a large proportion of JAK2 and MPL negative myelofibrosis and essential thrombocythemia (ET) patients.1, 2 The calreticulin gene encoding a 48 kDa protein is located on chromosome 19p13.3, and regulates key cellular functions like proliferation and apoptosis.3, 4 CALR mutations have been identified in 15.5 to 31.4% of unselected ET patients corresponding to 48.9–82% of JAK2/MPL negative ET patients,2, 5 and in 15.6–35% of unselected myelofibrosis patients, corresponding to 56–88% of JAK2/MPL negative myelofibrosis patients.1, 2 Thus, CALR mutations will become an important diagnostic marker for myeloproliferative neoplasms.6

Klampfl et al.1 showed that CALR mutated primary myelofibrosis (PMF) patients have lower white blood cell counts and higher platelet counts compared with JAK2 mutated patients and that these patients survive significantly longer than JAK2 and MPL mutated patients. In addition, Tefferi et al.7 reported an association of mutated CALR with younger age, lower Dynamic International Prognostic Scoring System (DIPSS)-plus risk score and low frequency of spliceosome mutations, and showed that CALR/JAK2/MPL triple negative patients had the worst prognosis.

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References

  1. Klampfl T, Gisslinger H, Harutyunyan AS, Nivarthi H, Rumi E, Milosevic JD et al. Somatic mutations of calreticulin in myeloproliferative neoplasms. N Engl J Med 2013; 369: 2379–2390.

    Article  CAS  Google Scholar 

  2. Nangalia J, Massie CE, Baxter EJ, Nice FL, Gundem G, Wedge DC et al. Somatic CALR mutations in myeloproliferative neoplasms with nonmutated JAK2. N Engl J Med 2013; 369: 2391–2405.

    Article  CAS  Google Scholar 

  3. 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.

    Article  CAS  Google Scholar 

  4. Chao MP, Majeti R, Weissman IL . Programmed cell removal: a new obstacle in the road to developing cancer. Nat Rev Cancer 2011; 12: 58–67.

    Article  Google Scholar 

  5. Rotunno G, Mannarelli C, Guglielmelli P, Pacilli A, Pancrazzi A, Pieri L et al. Impact of calreticulin mutations on clinical and hematological phenotype and outcome in essential thrombocythemia. Blood 2013;; e-pub ahead of print 26 December 2013.

  6. Tefferi A, Thiele J, Vannucchi AM, Barbui T . An overview on CALR and CSF3R mutations and a proposal for revision of WHO diagnostic criteria for myeloproliferative neoplasms. Leukemia 2014;; e-pub ahead of print 11 February 2014; doi:10.1038/leu.2014.35.

    Article  CAS  Google Scholar 

  7. Tefferi A, Lasho TL, Finke CM, Knudson RA, Ketterling R, Hanson CH et al. CALR vs JAK2 vs MPL-mutated or triple-negative myelofibrosis: clinical, cytogenetic and molecular comparisons. Leukemia 2014;; e-pub ahead of print 21 January 2014; doi:10.1038/leu.2014.3.

    Article  CAS  Google Scholar 

  8. Kroger N, Holler E, Kobbe G, Bornhauser M, Schwerdtfeger R, Baurmann H et al. Allogeneic stem cell transplantation after reduced-intensity conditioning in patients with myelofibrosis: a prospective, multicenter study of the Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation. Blood 2009; 114: 5264–5270.

    Article  Google Scholar 

  9. Alchalby H, Yunus DR, Zabelina T, Kobbe G, Holler E, Bornhauser M et al. Risk models predicting survival after reduced-intensity transplantation for myelofibrosis. Br J Haematol 2012; 157: 75–85.

    Article  Google Scholar 

  10. Alchalby H, Badbaran A, Zabelina T, Kobbe G, Hahn J, Wolff D et al. Impact of JAK2V617F mutation status, allele burden, and clearance after allogeneic stem cell transplantation for myelofibrosis. Blood 2010; 116: 3572–3581.

    Article  CAS  Google Scholar 

  11. 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.

    Article  CAS  Google Scholar 

  12. Gardai SJ, McPhillips KA, Frasch SC, Janssen WJ, Starefeldt A, Murphy-Ullrich JE et al. Cell-surface calreticulin initiates clearance of viable or apoptotic cells through trans-activation of LRP on the phagocyte. Cell 2005; 123: 321–334.

    Article  CAS  Google Scholar 

  13. Locher C, Rusakiewicz S, Tesniere A, Ghiringhelli F, Apetoh L, Kroemer G et al. Witch hunt against tumor cells enhanced by dendritic cells. Ann N Y Acad Sci 2009; 1174: 51–60.

    Article  CAS  Google Scholar 

  14. 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.

    Article  CAS  Google Scholar 

  15. Hussein K, Pardanani AD, Van Dyke DL, Hanson CA, Tefferi A . International Prognostic Scoring System-independent cytogenetic risk categorization in primary myelofibrosis. Blood 2010; 115: 496–499.

    Article  CAS  Google Scholar 

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Acknowledgements

We are indebted to all patients and contributing doctors. We thank Elke Dammann and Wolfgang Kühnau for support in sample and data acquisition. This study was supported by grants 109003, 110284, 110287 and 110292 from Deutsche Krebshilfe; grant DJCLS H09/1f, R 10/22, and SP 12/02 from the Deutsche-José-Carreras Leukämie-Stiftung e.V; the German Federal Ministry of Education and Research grant 01EO0802 (IFB-Tx); DFG grant HE 5240/5-1; and grants from Hamburger Krebsgesellschaft, Erich und Gertrud Roggenbuck Stiftung and Dieter-Schlag Stiftung.

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Author notes

  1. V Panagiota and F Thol: These authors contributed equally to this work.

  2. N Kröger and M Heuser: These authors share the senior authorship.

Authors and Affiliations

  1. Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany

    V Panagiota, F Thol, C Koenecke, R Shahswar, A Chaturvedi, M Stadler, M Eder, A Kloos, A Trummer, A Ganser & M Heuser

  2. Department of Cardiology, University Hospital Marburg, Marburg, Germany

    B Markus

  3. Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

    B Fehse, H Alchalby, A Badbaran & N Kröger

  4. Institute of Pathology, Hannover Medical School, Hannover, Germany

    U Lehmann & H-H Kreipe

  5. Institute of Cell and Molecular Pathology, Hannover Medical School, Hannover, Germany

    G Göhring & B Schlegelberger

  6. Outpatient Oncology Center Hannover, Hannover, Germany

    M Koenigsmann

  7. Department of Hematology, Oncology and Clinical Immunology, University of Duesseldorf, Medical Faculty, Duesseldorf, Germany

    T Schroeder & G Kobbe

  8. Medical Department I, University Hospital Carl Gustav Carus, Dresden, Germany

    C Thiede & U Platzbecker

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Correspondence to M Heuser.

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Panagiota, V., Thol, F., Markus, B. et al. Prognostic effect of calreticulin mutations in patients with myelofibrosis after allogeneic hematopoietic stem cell transplantation. Leukemia 28, 1552–1555 (2014). https://doi.org/10.1038/leu.2014.66

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