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Hereditary thrombocythemia due to splicing donor site mutation of THPO in a Japanese family

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Abstract

Thrombopoietin (THPO) is an essential factor for platelet production. Hereditary thrombocythemia (HT) is caused by a germline mutation of THPO, MPL, or JAK2 and is inherited in an autosomal-dominant manner. We identified a Japanese family with HT due to a point mutation of the splicing donor site of the THPO gene (THPO c.13 + 1G > A). Bone marrow biopsy showed increased megakaryocytes mimicking essential thrombocythemia. One affected family member developed chronic myeloid leukemia. We cloned the mutation and developed mutated and wild type THPO expression vectors. Molecular analysis showed that the mutation causes an exon 3 skipping transcript of THPO that abrogates a suppressive untranslated upstream open reading frame. Although the transcript levels of THPO mRNA were comparable, mutated transcripts were more efficiently translated and THPO protein expression was significantly higher than that of the wild type.

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Data availability

The data sets generated and/or analyzed during the current study are available from the corresponding author upon reasonable request.

References

  1. Kaushansky K (1998) Thrombopoietin. N Engl J Med 339(11):746–754. https://doi.org/10.1056/NEJM199809103391107

    Article  PubMed  CAS  Google Scholar 

  2. Kaushansky K (2006) Lineage-specific hematopoietic growth factors. N Engl J Med 354(19):2034–2045. https://doi.org/10.1056/NEJMra052706

    Article  PubMed  CAS  Google Scholar 

  3. Harrison CN, Gale RE, Wiestner AC, Skoda RC, Linch DC (1998) The activating splice mutation in intron 3 of the thrombopoietin gene is not found in patients with non-familial essential thrombocythaemia. Br J Haematol 102(5):1341–1343

    Article  PubMed  CAS  Google Scholar 

  4. Wiestner A, Schlemper RJ, van der Maas AP, Skoda RC (1998) An activating splice donor mutation in the thrombopoietin gene causes hereditary thrombocythaemia. Nat Genet 18(1):49–52. https://doi.org/10.1038/ng0198-49

    Article  PubMed  CAS  Google Scholar 

  5. Kondo T, Okabe M, Sanada M, Kurosawa M, Suzuki S, Kobayashi M, Hosokawa M, Asaka M (1998) Familial essential thrombocythemia associated with one-base deletion in the 5’-untranslated region of the thrombopoietin gene. Blood 92(4):1091–1096

    Article  PubMed  CAS  Google Scholar 

  6. Jorgensen MJ, Raskind WH, Wolff JF, Bachrach HR, Kaushansky K (1998) Familial thrombocytosis associated with overproduction of thrombopoietin due to a novel splice donor site mutation. Blood (ASH Meeting Abstracts) 92(205):Abstract #834

    Google Scholar 

  7. Ghilardi N, Wiestner A, Kikuchi M, Ohsaka A, Skoda RC (1999) Hereditary thrombocythaemia in a Japanese family is caused by a novel point mutation in the thrombopoietin gene. Br J Haematol 107(2):310–316. https://doi.org/10.1046/j.1365-2141.1999.01710.x

    Article  PubMed  CAS  Google Scholar 

  8. Ghilardi N, Skoda RC (1999) A single-base deletion in the thrombopoietin (TPO) gene causes familial essential thrombocythemia through a mechanism of more efficient translation of TPO mRNA. Blood 94(4):1480–1482

    Article  PubMed  CAS  Google Scholar 

  9. Liu K, Kralovics R, Rudzki Z, Grabowska B, Buser AS, Olcaydu D, Gisslinger H, Tiedt R, Frank P, Okon K, van der Maas AP, Skoda RC (2008) A de novo splice donor mutation in the thrombopoietin gene causes hereditary thrombocythemia in a Polish family. Haematologica 93(5):706–714. https://doi.org/10.3324/haematol.11801

    Article  PubMed  CAS  Google Scholar 

  10. Graziano C, Carone S, Panza E, Marino F, Magini P, Romeo G, Pession A, Seri M (2009) Association of hereditary thrombocythemia and distal limb defects with a thrombopoietin gene mutation. Blood 114(8):1655–1657. https://doi.org/10.1182/blood-2009-04-217851

    Article  PubMed  CAS  Google Scholar 

  11. Zhang B, Ng D, Jones C, Oh ST, Nolan GP, Salehi S, Wong W, Zehnder JL, Gotlib J (2011) A novel splice donor mutation in the thrombopoietin gene leads to exon 2 skipping in a Filipino family with hereditary thrombocythemia. Blood 118(26):6988–6990. https://doi.org/10.1182/blood-2011-10-386177

    Article  PubMed  Google Scholar 

  12. Stockklausner C, Echner N, Klotter AC, Hegenbart U, Dreger P, Kulozik AE (2012) Hereditary thrombocythemia caused by a thrombopoietin (THPO) gain-of-function mutation associated with multiple myeloma and congenital limb defects. Ann Hematol 91(7):1129–1133. https://doi.org/10.1007/s00277-012-1453-y

    Article  PubMed  Google Scholar 

  13. Prouzet-Mauleon V, Montibus B, Chauveau A, Hautin M, Migeon M, Ka C, Laharanne E, Bidet A, Corcos L, Lippert E (2020) A novel thrombopoietin (THPO) mutation altering mRNA splicing in a case of familial thrombocytosis. Br J Haematol 190(2):e104–e107. https://doi.org/10.1111/bjh.16742

    Article  PubMed  CAS  Google Scholar 

  14. Jung N, Kim DH, Ha JS, Shim YJ (2020) Thrombocythemia 1 with THPO variant (c.13+1G>A) diagnosed using targeted exome sequencing: first case in Korea. Ann Lab Med 40(4):341–344. https://doi.org/10.3343/alm.2020.40.4.341

    Article  PubMed  PubMed Central  Google Scholar 

  15. Moliterno AR, Williams DM, Gutierrez-Alamillo LI, Salvatori R, Ingersoll RG, Spivak JL (2004) Mpl Baltimore: a thrombopoietin receptor polymorphism associated with thrombocytosis. Proc Natl Acad Sci U S A 101(31):11444-11447.https://doi.org/10.1073/pnas.0404241101

  16. Ding J, Komatsu H, Iida S, Yano H, Kusumoto S, Inagaki A, Mori F, Ri M, Ito A, Wakita A, Ishida T, Nitta M, Ueda R (2009) The Asn505 mutation of the c-MPL gene, which causes familial essential thrombocythemia, induces autonomous homodimerization of the c-Mpl protein due to strong amino acid polarity. Blood 114(15):3325–3328. https://doi.org/10.1182/blood-2008-04-149047

    Article  PubMed  CAS  Google Scholar 

  17. Liu K, Martini M, Rocca B, Amos CI, Teofili L, Giona F, Ding J, Komatsu H, Larocca LM, Skoda RC (2009) Evidence for a founder effect of the MPL-S505N mutation in eight Italian pedigrees with hereditary thrombocythemia. Haematologica 94(10):1368–1374. https://doi.org/10.3324/haematol.2009.005918

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. el El-Harith HA, Roesl C, Ballmaier M, Germeshausen M, Frye-Boukhriss H, von Neuhoff N, Becker C, Nurnberg G, Nurnberg P, Ahmed MA, Hubener J, Schmidtke J, Welte K, Stuhrmann M (2009) Familial thrombocytosis caused by the novel germ-line mutation p.Pro106Leu in the MPL gene. Br J Haematol 144(2):185–194. https://doi.org/10.1111/j.1365-2141.2008.07430.x

    Article  PubMed  CAS  Google Scholar 

  19. Teofili L, Giona F, Torti L, Cenci T, Ricerca BM, Rumi C, Nunes V, Foa R, Leone G, Martini M, Larocca LM (2010) Hereditary thrombocytosis caused by MPLSer505Asn is associated with a high thrombotic risk, splenomegaly and progression to bone marrow fibrosis. Haematologica 95(1):65–70. https://doi.org/10.3324/haematol.2009.007542

    Article  PubMed  CAS  Google Scholar 

  20. Bellanne-Chantelot C, Mosca M, Marty C, Favier R, Vainchenker W, Plo I (2017) Identification of MPL R102P mutation in hereditary thrombocytosis. Front Endocrinol (Lausanne) 8:235. https://doi.org/10.3389/fendo.2017.00235

    Article  PubMed  Google Scholar 

  21. Al-Harbi T, Al-Zahrani M, Al-Balwi M, Al-Hazmi A, Alsuhaibani A, Aljafn N, Alsumari F, Aleshaiwi L, Alsuhibani A, Alqasim O, Ahmad N (2021) Clinical course of myeloproliferative leukaemia virus oncogene (MPL) mutation-associated familial thrombocytosis: a review of 64 paediatric and adult patients. Br J Haematol 194(5):893–898. https://doi.org/10.1111/bjh.17624

    Article  PubMed  CAS  Google Scholar 

  22. Rendo M, Cavacece C, Kou CJ, Beeler BW, Fenderson J (2022) Familial essential thrombocythemia with novel MPL L502G and G208K mutations. Cureus 14(3):e23220. https://doi.org/10.7759/cureus.23220

    Article  PubMed  PubMed Central  Google Scholar 

  23. Vasseur L, Favier R, Kim R, Rabian F, Cabannes-Hamy A, Cassinat B, Maslah N, Vasquez N, Clappier E, Kiladjian JJ, Boissel N (2023) Clonal evolution in hereditary thrombocytosis with MPL T487A mutation. Pediatr Blood Cancer 70(2):e29905. https://doi.org/10.1002/pbc.29905

    Article  PubMed  CAS  Google Scholar 

  24. Mead AJ, Rugless MJ, Jacobsen SE, Schuh A (2012) Germline JAK2 mutation in a family with hereditary thrombocytosis. N Engl J Med 366(10):967–969. https://doi.org/10.1056/NEJMc1200349

    Article  PubMed  CAS  Google Scholar 

  25. Etheridge SL, Cosgrove ME, Sangkhae V, Corbo LM, Roh ME, Seeliger MA, Chan EL, Hitchcock IS (2014) A novel activating, germline JAK2 mutation, JAK2R564Q, causes familial essential thrombocytosis. Blood 123(7):1059–1068. https://doi.org/10.1182/blood-2012-12-473777

    Article  PubMed  CAS  Google Scholar 

  26. Marty C, Saint-Martin C, Pecquet C, Grosjean S, Saliba J, Mouton C, Leroy E, Harutyunyan AS, Abgrall JF, Favier R, Toussaint A, Solary E, Kralovics R, Constantinescu SN, Najman A, Vainchenker W, Plo I, Bellanne-Chantelot C (2014) Germ-line JAK2 mutations in the kinase domain are responsible for hereditary thrombocytosis and are resistant to JAK2 and HSP90 inhibitors. Blood 123(9):1372–1383. https://doi.org/10.1182/blood-2013-05-504555

    Article  PubMed  CAS  Google Scholar 

  27. Rumi E, Harutyunyan AS, Casetti I, Pietra D, Nivarthi H, Moriggl R, Cleary C, Bagienski K, Astori C, Bellini M, Berg T, Passamonti F, Kralovics R, Cazzola M (2014) A novel germline JAK2 mutation in familial myeloproliferative neoplasms. Am J Hematol 89(1):117–118. https://doi.org/10.1002/ajh.23614

    Article  PubMed  CAS  Google Scholar 

  28. Yoshimitsu M, Hachiman M, Uchida Y, Arima N, Arai A, Kamada Y, Shide K, Ito M, Shimoda K, Ishitsuka K (2019) Essential thrombocytosis attributed to JAK2-T875N germline mutation. Int J Hematol 110(5):584–590. https://doi.org/10.1007/s12185-019-02725-8

    Article  PubMed  CAS  Google Scholar 

  29. Kanda Y (2013) Investigation of the freely available easy-to-use software “EZR” for medical statistics. Bone Marrow Transplant 48(3):452–458. https://doi.org/10.1038/bmt.2012.244

    Article  PubMed  CAS  Google Scholar 

  30. Han EY, Catherwood M, McMullin MF (2021) Hereditary thrombocytosis: the genetic landscape. Br J Haematol 194(6):1098–1105. https://doi.org/10.1111/bjh.17741

    Article  PubMed  Google Scholar 

  31. Nelson ND, Marcogliese A, Bergstrom K, Scheurer M, Mahoney D, Bertuch AA (2016) Thrombopoietin measurement as a key component in the evaluation of pediatric thrombocytosis. Pediatr Blood Cancer 63(8):1484–1487. https://doi.org/10.1002/pbc.26032

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. Fielder PJ, Hass P, Nagel M, Stefanich E, Widmer R, Bennett GL, Keller GA, de Sauvage FJ, Eaton D (1997) Human platelets as a model for the binding and degradation of thrombopoietin. Blood 89(8):2782–2788

    Article  PubMed  CAS  Google Scholar 

  33. Kuter DJ, Beeler DL, Rosenberg RD (1994) The purification of megapoietin: a physiological regulator of megakaryocyte growth and platelet production. Proc Natl Acad Sci U S A 91(23):11104-11108. https://doi.org/10.1073/pnas.91.23.11104

  34. Kuter DJ (2013) The biology of thrombopoietin and thrombopoietin receptor agonists. Int J Hematol 98(1):10–23. https://doi.org/10.1007/s12185-013-1382-0

    Article  PubMed  CAS  Google Scholar 

  35. Zhang Y, Xi X, Yu H, Yang L, Lin J, Yang W, Liu J, Fan X, Xu Y (2022) Chemically modified in-vitro-transcribed mRNA encoding thrombopoietin stimulates thrombopoiesis in mice. Mol Ther Nucleic Acids 29:657–671. https://doi.org/10.1016/j.omtn.2022.08.017

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. Teofili L, Larocca LM (2011) Advances in understanding the pathogenesis of familial thrombocythaemia. Br J Haematol 152(6):701–712. https://doi.org/10.1111/j.1365-2141.2010.08500.x

    Article  PubMed  CAS  Google Scholar 

  37. Posthuma HL, Skoda RC, Jacob FA, van der Maas AP, Valk PJ, Posthuma EF (2010) Hereditary thrombocytosis not as innocent as thought? Development into acute leukemia and myelofibrosis. Blood 116(17):3375–3376. https://doi.org/10.1182/blood-2010-06-290718

    Article  PubMed  CAS  Google Scholar 

  38. Kikuchi M, Tayama T, Hayakawa H, Takahashi I, Hoshino H, Ohsaka A (1995) Familial thrombocytosis. Br J Haematol 89(4):900–902

    Article  PubMed  CAS  Google Scholar 

  39. Piccin A, Corvetta D, Rovigatti U, Mazzoleni G, Pusceddu I, Svaldi M, Steurer M, Gastl G, Cortelazzo S (2014) Essential thrombocytemia progressing to Ph+ chronic myeloid leukemia with megakaryoblastic blasts, following anagrelide withdrawal. Platelets 25(8):646–647. https://doi.org/10.3109/09537104.2013.858112

    Article  PubMed  CAS  Google Scholar 

  40. Xia D, Hsi ED, Dal Cin P, Hasserjian RP (2019) Composite chronic myeloid leukemia and essential thrombocythemia with BCR-ABL1 fusion and CALR mutation. Am J Hematol 94(4):504–505. https://doi.org/10.1002/ajh.25249

    Article  PubMed  Google Scholar 

  41. Mizutani S, Kuroda J, Shimizu D, Horiike S, Taniwaki M (2010) Emergence of chronic myelogenous leukemia during treatment for essential thrombocythemia. Int J Hematol 91(3):516–521. https://doi.org/10.1007/s12185-010-0502-3

    Article  PubMed  Google Scholar 

  42. Schlemper RJ, van der Maas AP, Eikenboom JC (1994) Familial essential thrombocythemia: clinical characteristics of 11 cases in one family. Ann Hematol 68(3):153–158

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

We thank Dr. Hiroshi Ikeda (Sapporo Medical College) for providing information about ii1 patient under consent of family member.

Funding

This work was supported by research budget of Department of Hematology, Hokkaido University Faculty of Medicine.

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Authors and Affiliations

  1. Department of Hematology, Hokkaido University Faculty of Medicine, Graduate School of Medicine, Kita 15, Nishi 7, Kita-Ku, Sapporo, Japan

    Hiroyuki Kimura, Masahiro Onozawa, Junichi Hashiguchi, Daisuke Hidaka, Toshihiro Matsukawa & Takanori Teshima

  2. Blood Disorders Center, Aiiku Hospital, Sapporo, Japan

    Minoru Kanaya & Takeshi Kondo

  3. Department of Surgical Pathology, Hokkaido University Hospital, Sapporo, Japan

    Hiromi Okada & Yoshihiro Matsuno

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  1. Hiroyuki Kimura
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Contributions

H. K. and M. O. designed the study, analyzed the data, and wrote the manuscript. H. K., J. H., and D. H. performed experiments. H. O. and Y. M. verified pathological finding of bone marrow biopsy. M. K., T. M., and K. T. were involved in the critical evaluation of the manuscript and data presentation. T. T. revised and approved the manuscript.

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Correspondence to Masahiro Onozawa.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This study was approved by the Institutional Review Board of Hokkaido University Faculty of Medicine (IRB#17–037).

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Informed consent was obtained from all individual participants included in the study. Written informed consent was obtained from each family member in accordance with the Declaration of Helsinki.

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Kimura, H., Onozawa, M., Hashiguchi, J. et al. Hereditary thrombocythemia due to splicing donor site mutation of THPO in a Japanese family. Ann Hematol 103, 89–96 (2024). https://doi.org/10.1007/s00277-023-05523-9

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