Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review
  • Published:

An overview on CALR and CSF3R mutations and a proposal for revision of WHO diagnostic criteria for myeloproliferative neoplasms

Leukemia volume 28, pages 1407–1413 (2014)Cite this article

Subjects

Abstract

Disease-specific mutations facilitate diagnostic precision and drug target discovery. In myeloproliferative neoplasms (MPN), this is best exemplified by the chronic myeloid leukemia-associated BCR-ABL1. No other mutation in MPN has thus far shown a similar degree of diagnostic accuracy or therapeutic relevance. However, JAK2 and KIT mutations are detected in more than 90% of patients with polycythemia vera and systemic mastocytosis, respectively, and are therefore used as highly sensitive clonal markers in these diseases. JAK2 and MPL mutations also occur in essential thrombocythemia (ET) and primary myelofibrosis (PMF), but their diagnostic value is limited by suboptimal sensitivity and specificity. The molecular diagnostic gap in JAK2/MPL-unmutated ET/PMF is now partially addressed by the recent discovery of calreticulin (CALR) mutations in the majority of such cases. However, bone marrow morphology remains the central diagnostic platform and is essential for distinguishing ET from prefibrotic PMF and diagnosing patients those do not express JAK2, MPL or CALR (triple-negative). The year 2013 was also marked by the description of CSF3R mutations in the majority of patients with chronic neutrophilic leukemia (CNL). Herein, we argue for the inclusion of CALR and CSF3R mutations in the World Health Organization classification system for ET/PMF and CNL, respectively.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  1. Swerdlow SHCE, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J et al. WHO Classification Of Tumours Of Haematopoietic And Lymhoid Tissues. IARC press: Lyon, France, 2008.

    Google Scholar 

  2. 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 (5): 937–951.

    Article  CAS  PubMed  Google Scholar 

  3. Heller P, Kornblihtt LI, Cuello MT, Larripa I, Najfeld V, Molinas FC . BCR-ABL transcripts may be detected in essential thrombocythemia but lack clinical significance. Blood 2001; 98: 1990.

    Article  CAS  PubMed  Google Scholar 

  4. Pieri L, Spolverini A, Scappini B, Occhini U, Birtolo S, Bosi A et al. Concomitant occurrence of BCR-ABL and JAK2V617F mutation. Blood 2011; 118: 3445–3446.

    Article  CAS  PubMed  Google Scholar 

  5. Thiele J, Kvasnicka HM, Fischer R . Bone marrow histopathology in chronic myelogenous leukemia (CML)-evaluation of distinctive features with clinical impact. Histol Histopathol 1999; 14: 1241–1256.

    CAS  PubMed  Google Scholar 

  6. Granger JM, Kontoyiannis DP . Etiology and outcome of extreme leukocytosis in 758 nonhematologic cancer patients: a retrospective, single-institution study. Cancer 2009; 115: 3919–3923.

    Article  PubMed  Google Scholar 

  7. Scott LM, Tong W, Levine RL, Scott MA, Beer PA, Stratton MR et al. JAK2 exon 12 mutations in polycythemia vera and idiopathic erythrocytosis. New Engl J Med 2007; 356: 459–468.

    Article  CAS  PubMed  Google Scholar 

  8. Tefferi A, Lasho TL, Abdel-Wahab O, Guglielmelli P, Patel J, Caramazza D et al. IDH1 and IDH2 mutation studies in 1473 patients with chronic-, fibrotic- or blast-phase essential thrombocythemia, polycythemia vera or myelofibrosis. Leukemia 2010; 24: 1302–1309.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. 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.

    Article  CAS  PubMed  Google Scholar 

  10. 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 doi:10.1182/blood-2013-11-538983.

    Article  PubMed  Google Scholar 

  11. 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  PubMed  Google Scholar 

  12. Pikman Y, Lee BH, Mercher T, McDowell E, Ebert BL, Gozo M et al. MPLW515L is a novel somatic activating mutation in myelofibrosis with myeloid metaplasia. PLoS Med 2006; 3: e270.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Pardanani AD, Levine RL, Lasho T, Pikman Y, Mesa RA, Wadleigh M et al. MPL515 mutations in myeloproliferative and other myeloid disorders: a study of 1182 patients. Blood 2006; 108: 3472–3476.

    Article  CAS  PubMed  Google Scholar 

  14. 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.

    Article  CAS  PubMed  Google Scholar 

  15. 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.

    Article  CAS  PubMed  Google Scholar 

  16. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Rumi E, Pietra D, Ferretti V, Klampfl T, Harutyunyan AS, Milosevic JD et al. JAK2 or CALR mutation status defines subtypes of essential thrombocythemia with substantially different clinical course and outcomes. Blood 2013; e-pub ahead of print 23 December 2013 doi:10.1182/blood-2013-11-539098.

    Article  PubMed  Google Scholar 

  18. Chi J, Nicolaou KA, Nicolaidou V, Kouma L, Mitsidou A, Pierides C et al. Calreticulin exon 9 frameshift mutations in patients with thrombocytosis. Leukemia 2013; e-pub ahead of print 17 January 2014 doi:10.1038/leu.2013.382.

    Article  PubMed  Google Scholar 

  19. Vandenberghe P, Beel K . Severe congenital neutropenia, a genetically heterogeneous disease group with an increased risk of AML/MDS. Pediatr Rep 2011; 3 (Suppl 2): e9.

    PubMed  PubMed Central  Google Scholar 

  20. Germeshausen M, Ballmaier M, Welte K . Incidence of CSF3R mutations in severe congenital neutropenia and relevance for leukemogenesis: Results of a long-term survey. Blood 2007; 109: 93–99.

    Article  CAS  PubMed  Google Scholar 

  21. Plo I, Zhang Y, Le Couedic JP, Nakatake M, Boulet JM, Itaya M et al. An activating mutation in the CSF3R gene induces a hereditary chronic neutrophilia. J Exp Med 2009; 206: 1701–1707.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Forbes LV, Gale RE, Pizzey A, Pouwels K, Nathwani A, Linch DC . An activating mutation in the transmembrane domain of the granulocyte colony-stimulating factor receptor in patients with acute myeloid leukemia. Oncogene 2002; 21: 5981–5989.

    Article  CAS  PubMed  Google Scholar 

  23. Beekman R, Valkhof MG, Sanders MA, van Strien PM, Haanstra JR, Broeders L et al. Sequential gain of mutations in severe congenital neutropenia progressing to acute myeloid leukemia. Blood 2012; 119: 5071–5077.

    Article  CAS  PubMed  Google Scholar 

  24. Maxson JE, Gotlib J, Pollyea DA, Fleischman AG, Agarwal A, Eide CA et al. Oncogenic CSF3R mutations in chronic neutrophilic leukemia and atypical CML. New Engl J Med 2013; 368: 1781–1790.

    Article  CAS  PubMed  Google Scholar 

  25. Fleischman AG, Maxson JE, Luty SB, Agarwal A, Royer LR, Abel ML et al. The CSF3R T618I mutation causes a lethal neutrophilic neoplasia in mice that is responsive to therapeutic JAK inhibition. Blood 2013; 122: 3628–3631.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Pardanani A, Lasho TL, Laborde RR, Elliott M, Hanson CA, Knudson RA et al. CSF3R T618I is a highly prevalent and specific mutation in chronic neutrophilic leukemia. Leukemia 2013; 27: 1870–1873.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Beekman R, Valkhof M, van Strien P, Valk PJ, Touw IP . Prevalence of a new auto-activating colony stimulating factor 3 receptor mutation (CSF3R-T595I) in acute myeloid leukemia and severe congenital neutropenia. Haematologica 2013; 98: e62–e63.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Kosmider O, Itzykson R, Chesnais V, Lasho T, Laborde R, Knudson R et al. Mutation of the colony-stimulating factor-3 receptor gene is a rare event with poor prognosis in chronic myelomonocytic leukemia. Leukemia 2013; 27: 1946–1949.

    Article  CAS  PubMed  Google Scholar 

  29. James C, Ugo V, Le Couedic JP, Staerk J, Delhommeau F, Lacout C et al. A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature 2005; 434: 1144–1148.

    Article  CAS  PubMed  Google Scholar 

  30. Pardanani A, Lasho TL, Finke C, Hanson CA, Tefferi A . Prevalence and clinicopathologic correlates of JAK2 exon 12 mutations in JAK2V617F-negative polycythemia vera. Leukemia 2007; 21: 1960–1963.

    Article  CAS  PubMed  Google Scholar 

  31. Tefferi A, Rumi E, Finazzi G, Gisslinger H, Vannucchi AM, Rodeghiero F et al. Survival and prognosis among 1545 patients with contemporary polycythemia vera: an international study. Leukemia 2013; 27: 1874–1881.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Shih LY, Lee CT . Identification of masked polycythemia vera from patients with idiopathic marked thrombocytosis by endogenous erythroid colony assay. Blood 1994; 83: 744–748.

    CAS  PubMed  Google Scholar 

  33. Barbui T, Thiele J, Gisslinger H, Finazzi G, Carobbio A, Rumi E et al. Masked polycythemia vera (mPV): results of an international study. Am J Hematol 2014; 89: 52–54.

    Article  CAS  PubMed  Google Scholar 

  34. Barbui T, Thiele J, Vannucchi AM, Tefferi A . Rethinking the diagnostic criteria of polycythemia vera. Leukemia 2013; e-pub ahead of print 17 January 2014 doi:10.1038/leu.2013.380.

    Article  PubMed  Google Scholar 

  35. Marchioli R, Finazzi G, Specchia G, Cacciola R, Cavazzina R, Cilloni D et al. Cardiovascular events and intensity of treatment in polycythemia vera. New Engl J Med 2013; 368: 22–33.

    Article  CAS  PubMed  Google Scholar 

  36. Tefferi A, Barbui T . Personalized management of essential thrombocythemia-application of recent evidence to clinical practice. Leukemia 2013; 27: 1617–1620.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Elliott MA, Tefferi A . The molecular genetics of chronic neutrophilic leukaemia: defining a new era in diagnosis and therapy. Curr Opin Hematol 2013; e-pub ahead of print 11 December 2013 doi:10.1097/MOH.0000000000000014.

    Article  CAS  PubMed  Google Scholar 

  38. Bohm J, Schaefer HE . Chronic neutrophilic leukaemia: 14 new cases of an uncommon myeloproliferative disease. J Clin Pathol 2002; 55: 862–864.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Engstrom PF, Bloom MG, Demetri GD, Febbo PG, Goeckeler W, Ladanyi M et al. NCCN molecular testing white paper: effectiveness, efficiency, and reimbursement. J Natl Compr Canc Netw 2011; 9 (Suppl 6): S1–16.

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

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

    A Tefferi

  2. Department of Pathology, University of Cologne, Cologne, Germany

    J Thiele

  3. Department of Hematology, University of Florence, Florence, Italy

    A M Vannucchi

  4. Division of Hematology and Research Foundation, Papa Giovanni XXIII Hospital, Bergamo, Italy

    T Barbui

Authors
  1. A Tefferi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. J Thiele
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. A M Vannucchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. T Barbui
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to A Tefferi.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Tefferi, A., Thiele, J., Vannucchi, A. et al. An overview on CALR and CSF3R mutations and a proposal for revision of WHO diagnostic criteria for myeloproliferative neoplasms. Leukemia 28, 1407–1413 (2014). https://doi.org/10.1038/leu.2014.35

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/leu.2014.35

Keywords

This article is cited by

Search

Advanced search

Quick links