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A rare CALR variant mutation and a review of CALR in essential thrombocythemia

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Abstract

Essential thrombocythemia (ET) is an indolent myeloproliferative neoplasm characterized by megakaryocyte hyperplasia, thrombocytosis, thrombotic and hemorrhagic complications, and potential transformation into myelofibrosis and acute myeloid leukemia. The vast majority of cases are driven by a somatic mutation in JAK2, CALR, or MPL. CALR, a gene that codes for the calcium-binding chaperone calreticulin, is the predominant mutation in patients with non-mutated JAK2 essential thrombocythemia, accounting for 20–25% of the overall somatic mutation frequency in ET. In this brief review of ET, we introduce a rare CALR mutation through a case presentation of a 58-year-old man with diffuse pulmonary emboli in the setting of thrombocytosis. We subsequently characterize the main types of CALR mutations and their value in diagnosis and prognosis of disease course, and lastly discuss the current clinical approach to ET.

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References

  1. Deadmond MA, Smith-Gagen JA (2015) Changing incidence of myeloproliferative neoplasms: trends and subgroup risk profiles in the USA, 1973–2011. J Cancer Res Clin Oncol 141(12):2131–2138. https://doi.org/10.1007/s00432-015-1983-5

    Article  PubMed  Google Scholar 

  2. Tefferi A, Barbui T (2015) Essential thrombocythemia and polycythemia vera: focus on clinical practice. Mayo Clin Proc 90(9):1283–1293. https://doi.org/10.1016/j.mayocp.2015.05.014

    Article  PubMed  Google Scholar 

  3. Elliott MA, Tefferi A (2005) Thrombosis and haemorrhage in polycythaemia vera and essential thrombocythaemia. Br J Haematol 128(3):275–290. https://doi.org/10.1111/j.1365-2141.2004.05277.x

    Article  CAS  PubMed  Google Scholar 

  4. Gangat N, Wolanskyj AP, Tefferi A (2006) Abdominal vein thrombosis in essential thrombocythemia: prevalence, clinical correlates, and prognostic implications. Eur J Haematol 77(4):327–333. https://doi.org/10.1111/j.1600-0609.2006.00715.x

    Article  PubMed  Google Scholar 

  5. Klampfl T, Gisslinger H, Harutyunyan AS, Nivarthi H, Rumi E, Milosevic JD, Them NC, Berg T, Gisslinger B, Pietra D, Chen D, Vladimer GI, Bagienski K, Milanesi C, Casetti IC, Sant’Antonio E, Ferretti V, Elena C, Schischlik F, Cleary C, Six M, Schalling M, Schonegger A, Bock C, Malcovati L, Pascutto C, Superti-Furga G, Cazzola M, Kralovics R (2013) Somatic mutations of calreticulin in myeloproliferative neoplasms. N Engl J Med 369(25):2379–2390. https://doi.org/10.1056/NEJMoa1311347

    Article  CAS  PubMed  Google Scholar 

  6. Nangalia J, Massie CE, Baxter EJ, Nice FL, Gundem G, Wedge DC, Avezov E, Li J, Kollmann K, Kent DG, Aziz A, Godfrey AL, Hinton J, Martincorena I, Van Loo P, Jones AV, Guglielmelli P, Tarpey P, Harding HP, Fitzpatrick JD, Goudie CT, Ortmann CA, Loughran SJ, Raine K, Jones DR, Butler AP, Teague JW, O’Meara S, McLaren S, Bianchi M, Silber Y, Dimitropoulou D, Bloxham D, Mudie L, Maddison M, Robinson B, Keohane C, Maclean C, Hill K, Orchard K, Tauro S, Du MQ, Greaves M, Bowen D, Huntly BJ, Harrison CN, Cross NC, Ron D, Vannucchi AM, Papaemmanuil E, Campbell PJ, Green AR (2013) Somatic CALR mutations in myeloproliferative neoplasms with nonmutated JAK2. N Engl J Med 369(25):2391–2405. https://doi.org/10.1056/NEJMoa1312542

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Chen CC, Gau JP, Chou HJ, You JY, Huang CE, Chen YY, Lung J, Chou YS, Leu YW, Lu CH, Lee KD, Tsai YH (2014) Frequencies, clinical characteristics, and outcome of somatic CALR mutations in JAK2-unmutated essential thrombocythemia. Ann Hematol 93(12):2029–2036. https://doi.org/10.1007/s00277-014-2151-8

    Article  CAS  PubMed  Google Scholar 

  8. Rotunno G, Mannarelli C, Guglielmelli P, Pacilli A, Pancrazzi A, Pieri L, Fanelli T, Bosi A, Vannucchi AM, Associazione Italiana per la Ricerca sul Cancro Gruppo Italiano Malattie Mieloproliferative I (2014) Impact of calreticulin mutations on clinical and hematological phenotype and outcome in essential thrombocythemia. Blood 123 (10):1552–1555. https://doi.org/10.1182/blood-2013-11-538983

    Article  CAS  PubMed  Google Scholar 

  9. CALR calreticulin [Internet]. Bethesda (MD): National Library of Medicine (US), National Center for Biotechnology Information; 2004 – [cited 2017/05/20]. https://www.ncbi.nlm.nih.gov/gene/811

  10. Pietra D, Rumi E, Ferretti VV, Di Buduo CA, Milanesi C, Cavalloni C, Sant’Antonio E, Abbonante V, Moccia F, Casetti IC, Bellini M, Renna MC, Roncoroni E, Fugazza E, Astori C, Boveri E, Rosti V, Barosi G, Balduini A, Cazzola M (2016) Differential clinical effects of different mutation subtypes in CALR-mutant myeloproliferative neoplasms. Leukemia 30(2):431–438. https://doi.org/10.1038/leu.2015.277

    Article  CAS  PubMed  Google Scholar 

  11. Luo W, Yu Z (2015) Calreticulin (CALR) mutation in myeloproliferative neoplasms (MPNs). Stem Cell Investig 2:16. https://doi.org/10.3978/j.issn.2306-9759.2015.08.01

    PubMed  PubMed Central  Google Scholar 

  12. Ha JS, Kim YK (2015) Calreticulin exon 9 mutations in myeloproliferative neoplasms. Ann Lab Med 35(1):22–27. https://doi.org/10.3343/alm.2015.35.1.22

    Article  CAS  PubMed  Google Scholar 

  13. Kollmann K, Warsch W, Gonzalez-Arias C, Nice FL, Avezov E, Milburn J, Li J, Dimitropoulou D, Biddie S, Wang M, Poynton E, Colzani M, Tijssen MR, Anand S, McDermott U, Huntly B, Green T (2017) A novel signalling screen demonstrates that CALR mutations activate essential MAPK signalling and facilitate megakaryocyte differentiation. Leukemia 31(4):934–944. https://doi.org/10.1038/leu.2016.280

    Article  CAS  PubMed  Google Scholar 

  14. Lau WW, Hannah R, Green AR, Gottgens B (2015) The JAK-STAT signaling pathway is differentially activated in CALR-positive compared with JAK2V617F-positive ET patients. Blood 125(10):1679–1681. https://doi.org/10.1182/blood-2014-12-618074

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Tefferi A, Wassie EA, Guglielmelli P, Gangat N, Belachew AA, Lasho TL, Finke C, Ketterling RP, Hanson CA, Pardanani A, Wolanskyj AP, Maffioli M, Casalone R, Pacilli A, Vannucchi AM, Passamonti F (2014) Type 1 versus Type 2 calreticulin mutations in essential thrombocythemia: a collaborative study of 1027 patients. Am J Hematol 89(8):E121–E124. https://doi.org/10.1002/ajh.23743

    Article  CAS  PubMed  Google Scholar 

  16. Rumi E, Pietra D, Pascutto C, Guglielmelli P, Martinez-Trillos A, Casetti I, Colomer D, Pieri L, Pratcorona M, Rotunno G, Sant’Antonio E, Bellini M, Cavalloni C, Mannarelli C, Milanesi C, Boveri E, Ferretti V, Astori C, Rosti V, Cervantes F, Barosi G, Vannucchi AM, Cazzola M, Associazione Italiana per la Ricerca sul Cancro Gruppo Italiano Malattie Mieloproliferative (2014) Clinical effect of driver mutations of JAK2, CALR, or MPL in primary myelofibrosis. Blood 124(7):1062–1069. https://doi.org/10.1182/blood-2014-05-578435

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Barbui T, Thiele J, Vannucchi AM, Tefferi A (2015) Rationale for revision and proposed changes of the WHO diagnostic criteria for polycythemia vera, essential thrombocythemia and primary myelofibrosis. Blood Cancer J 5:e337. https://doi.org/10.1038/bcj.2015.64

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Tefferi A, Pardanani A (2014) Genetics: CALR mutations and a new diagnostic algorithm for MPN. Nat Rev Clin Oncol 11(3):125–126. https://doi.org/10.1038/nrclinonc.2014.16

    Article  CAS  PubMed  Google Scholar 

  19. Finazzi G, Carobbio A, Guglielmelli P, Cavalloni C, Salmoiraghi S, Vannucchi AM, Cazzola M, Passamonti F, Rambaldi A, Barbui T (2014) Calreticulin mutation does not modify the IPSET score for predicting the risk of thrombosis among 1150 patients with essential thrombocythemia. Blood 124(16):2611–2612. https://doi.org/10.1182/blood-2014-08-596676

    Article  CAS  PubMed  Google Scholar 

  20. Tefferi A, Barbui T (2015) Polycythemia vera and essential thrombocythemia: 2015 update on diagnosis, risk-stratification and management. Am J Hematol 90(2):162–173. https://doi.org/10.1002/ajh.23895

    Article  CAS  PubMed  Google Scholar 

  21. Angona A, Fernandez-Rodriguez C, Alvarez-Larran A, Camacho L, Longaron R, Torres E, Pairet S, Besses C, Bellosillo B (2016) Molecular characterisation of triple negative essential thrombocythaemia patients by platelet analysis and targeted sequencing. Blood Cancer J 6(8):e463. https://doi.org/10.1038/bcj.2016.75

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Yao QM, Zhou J, Gale RP, Li JL, Li LD, Li N, Chen SS, Ruan GR (2015) A rapid, highly accurate method for quantifying CALR mutant allele burden in persons with myeloproliferative neoplasms. Hematology 20(9):517–522. https://doi.org/10.1179/1607845415Y.0000000009

    Article  PubMed  Google Scholar 

  23. Barbui T, Thiele J, Passamonti F, Rumi E, Boveri E, Ruggeri M, Rodeghiero F, d’Amore ES, Randi ML, Bertozzi I, Marino F, Vannucchi AM, Antonioli E, Carrai V, Gisslinger H, Buxhofer-Ausch V, Mullauer L, Carobbio A, Gianatti A, Gangat N, Hanson CA, Tefferi A (2011) Survival and disease progression in essential thrombocythemia are significantly influenced by accurate morphologic diagnosis: an international study. J Clin Oncol 29(23):3179–3184. https://doi.org/10.1200/JCO.2010.34.5298

    Article  PubMed  Google Scholar 

  24. Barbui T, Finazzi G, Carobbio A, Thiele J, Passamonti F, Rumi E, Ruggeri M, Rodeghiero F, Randi ML, Bertozzi I, Gisslinger H, Buxhofer-Ausch V, De Stefano V, Betti S, Rambaldi A, Vannucchi AM, Tefferi A (2012) Development and validation of an International Prognostic Score of thrombosis in World Health Organization-essential thrombocythemia (IPSET-thrombosis). Blood 120(26):5128–5133. https://doi.org/10.1182/blood-2012-07-444067 (quiz 5252)

    Article  CAS  PubMed  Google Scholar 

  25. Barbui T, Vannucchi AM, Buxhofer-Ausch V, De Stefano V, Betti S, Rambaldi A, Rumi E, Ruggeri M, Rodeghiero F, Randi ML, Bertozzi I, Gisslinger H, Finazzi G, Carobbio A, Thiele J, Passamonti F, Falcone C, Tefferi A (2015) Practice-relevant revision of IPSET-thrombosis based on 1019 patients with WHO-defined essential thrombocythemia. Blood Cancer J 5:e369. https://doi.org/10.1038/bcj.2015.94

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Rumi E, Cazzola M (2016) How I treat essential thrombocythemia. Blood 128(20):2403–2414. https://doi.org/10.1182/blood-2016-05-643346

    Article  CAS  PubMed  Google Scholar 

  27. Patrono C, Rocca B, De Stefano V (2013) Platelet activation and inhibition in polycythemia vera and essential thrombocythemia. Blood 121(10):1701–1711. https://doi.org/10.1182/blood-2012-10-429134

    Article  CAS  PubMed  Google Scholar 

  28. Duvall D (2011) Therapeutic cytapheresis: too many platelets, too many white blood cells. J Clin Apher 26(1):47–52. https://doi.org/10.1002/jca.20266

    Article  PubMed  Google Scholar 

  29. Pieri L, Pancrazzi A, Pacilli A, Rabuzzi C, Rotunno G, Fanelli T, Guglielmelli P, Fjerza R, Paoli C, Verstovsek S, Vannucchi AM (2015) JAK2V617F complete molecular remission in polycythemia vera/essential thrombocythemia patients treated with ruxolitinib. Blood 125(21):3352–3353. https://doi.org/10.1182/blood-2015-01-624536

    Article  CAS  PubMed  Google Scholar 

  30. Lin Y, Liu E, Sun Q, Ma J, Li Q, Cao Z, Wang J, Jia Y, Zhang H, Song Z, Ai X, Shi L, Feng X, Li C, Wang J, Ru K (2015) The prevalence of JAK2, MPL, and CALR mutations in chinese patients with BCR-ABL1-negative myeloproliferative neoplasms. Am J Clin Pathol 144(1):165–171. https://doi.org/10.1309/AJCPALP51XDIXDDV

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Medicine, Duke University Medical Center, Durham, NC, USA

    Robert Diep

  2. Division of Hematology, Department of Medicine, Duke University Medical Center, Durham, NC, USA

    Ara Metjian

  3. Duke University Health System, DUMC 3912, Durham, NC, 27710, USA

    Robert Diep & Ara Metjian

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  1. Robert Diep
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Correspondence to Robert Diep.

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In keeping with the Duke IRB policy, the review of medical records for publication of a single case report is not considered to be research involving human subjects, and therefore such a report does not require IRB review and approval.

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Diep, R., Metjian, A. A rare CALR variant mutation and a review of CALR in essential thrombocythemia. J Thromb Thrombolysis 45, 457–462 (2018). https://doi.org/10.1007/s11239-018-1619-0

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