WT1 Gene Overexpression in Differential Diagnosis of Ph-negative Myeloproliferative Disorders

E.G. Lomaia, Nadiya Tamazovna Siordiya, E.G. Lisina, O.M. Senderova, A.A. Silyutina, A.Yu. Zaritskey,

DOI:

https://doi.org/10.21320/2500-2139-2019-12-3-297-302

Aim. To assess the rate of WT1 gene overexpression and its clinical value in Ph-negative myeloproliferative disorders (MPD).

Materials & Methods. The trial included 72 patents with Ph-negative MPD. Among them there were patients with primary myelofibrosis (MF; n = 32), post-polycythemia vera MF (n = 7), polycythemia vera (PV; n = 17), and essential thrombocythemia (ET; n = 16) with median age of 57 years (range 19–78 years). Median (range) time from diagnosis to the date of evaluating WT1 expression in PV, ET, and MF was 9.4 (0–309), 14.4 (0–55), and 21.4 months (0–271 months), respectively. WT1 expression in terms of WT1 copies/104 ABL copies was measured by quantitative PCR.

Results. WT1 gene overexpression is revealed solely in patients with MF (in 34/39; 87 %). In PV/ET no WT1 gene overexpression was observed. Median WT1 expression in MF was 230/104 ABL copies (range 42.2–9,316.45/104 ABL copies). Sensitivity and specificity of WT1 gene overexpression in MF with respect to PV/ET were 87 % and 100 %, respectively. A distinct correlation was identified between WT1 gene expression level and spleen size, duration of the disease, blast cell count, and DIPSS risk group. WT1 gene expression level could be correlated neither with age and sex, nor with MF mutation status and leucocyte, thrombocyte, and haemoglobin levels.

Conclusion It appears that due to a high specificity and sensitivity of WT1 gene expression in MF it can be used as a marker for differential diagnosis of Ph-negative MPD. A correlation between WT1 gene expression and tumor mass in MF cannot be excluded. It is advisable to analyze the dynamics of WT1 expression level to predict the efficacy of current targeted therapy.

  • E.G. Lomaia VA Almazov National Medical Research Center, 2 Akkuratova str., Saint Petersburg, Russian Federation, 197341 ; ФГБУ «НМИЦ им. В.А. Алмазова» Минздрава России, ул. Аккуратова, д. 2, Санкт-Петербург, Российская Федерация, 197341
  • Nadiya Tamazovna Siordiya VA Almazov National Medical Research Center, 2 Akkuratova str., Saint Petersburg, Russian Federation, 197341 ; ФГБУ «НМИЦ им. В.А. Алмазова» Минздрава России, ул. Аккуратова, д. 2, Санкт-Петербург, Российская Федерация, 197341
  • E.G. Lisina Municipal Clinical Hospital No. 52, 3 Pekhotnaya str., Moscow, Russian Federation, 123182 ; ГБУЗ «Городская клиническая больница № 52 ДЗМ», ул. Пехотная, д. 3, Москва, Российская Федерация, 123182
  • O.M. Senderova Irkutsk Regional Clinical Hospital, 100 Yubileinyi microdistrict, Irkutsk, Russian Federation, 664049 ; ГБУЗ «Иркутская ордена “Знак Почета” областная клиническая больница», микрорайон Юбилейный, д. 100, Иркутск, Российская Федерация, 664049
  • A.A. Silyutina VA Almazov National Medical Research Center, 2 Akkuratova str., Saint Petersburg, Russian Federation, 197341 ; ФГБУ «НМИЦ им. В.А. Алмазова» Минздрава России, ул. Аккуратова, д. 2, Санкт-Петербург, Российская Федерация, 197341
  • A.Yu. Zaritskey VA Almazov National Medical Research Center, 2 Akkuratova str., Saint Petersburg, Russian Federation, 197341 ; ФГБУ «НМИЦ им. В.А. Алмазова» Минздрава России, ул. Аккуратова, д. 2, Санкт-Петербург, Российская Федерация, 197341
  1. Han Y, San-Marina S, Liu J, et al. Transcriptional activation of c-myc proto-oncogene by WT1 protein. Oncogene. 2004;23(41):6933–41. doi: 10.1038/sj.onc.1207609. DOI: https://doi.org/10.1038/sj.onc.1207609
  2. Hewitt SM, Hamada S, McDonnell TJ, et al. Regulation of the proto-oncogenes bcl-2 and c-myc by the Wilms’ tumor suppressor gene WT1. Cancer Res. 1995;55(22):5386–9.
  3. Jin DK, Kang SJ, Kim SJ, et al. Transcriptional regulation of PDGF-A and TGF-beta by +KTS WT1 deletion mutants and a mutant mimicking Denys-Drash syndrome. Ren Fail. 1999;21(6):685–94. DOI: https://doi.org/10.3109/08860229909094162
  4. Harrington MA, Konicek B, Song A, et al. Inhibition of colony-stimulating factor-1 promoter activity by the product of the Wilms’ tumor locus. J Biol Chem. 1993;268(28):21271–5. DOI: https://doi.org/10.1016/S0021-9258(19)36920-0
  5. Hu Q, Gao F, Tian W, et al. Wt1 ablation and Igf2 upregulation in mice result in Wilms tumors with elevated ERK1/2 phosphorylation. J Clin Invest. 2011;121(1):174–83. doi: 10.1172/JCI43772 DOI: https://doi.org/10.1172/JCI43772
  6. Maurer U, Brieger J, Weidmann E, et al. The Wilms’ tumor gene is expressed in a subset of CD34+ progenitors and downregulated early in the course of differentiation in vitro. Exp Hematol. 1997;25(9):945–50.
  7. Baird PN, Simmons PJ. Expression of the Wilms’ tumor gene (WT1) in normal hemopoiesis. Exp Hematol. 1997;25(4):312–20.
  8. King-Underwood L, Renshaw J, Pritchard-Jones K. Mutations in the Wilms’ tumor gene WT1 in leukemias. Blood. 1996;87(6):2171–9. DOI: https://doi.org/10.1182/blood.V87.6.2171.bloodjournal8762171
  9. Ho PA, Zeng R, Alonzo TA, et al. Prevalence and prognostic implications of WT1 mutations in pediatric acute myeloid leukemia (AML): a report from the Children’s Oncology Group. Blood. 2010;116(5):702–10. doi: 10.1182/blood-2010-02-268953. DOI: https://doi.org/10.1182/blood-2010-02-268953
  10. Tamaki H, Ogawa H, Ohyashiki K, et al. The Wilms’ tumor gene WT1 is a good marker for diagnosis of disease progression of myelodysplastic syndromes. Leukemia. 1999;13(3):393–9. doi: 10.1038/sj.leu.2401341. DOI: https://doi.org/10.1038/sj.leu.2401341
  11. Miwa H, Beran M, Saunders GF. Expression of the Wilms’ tumor gene (WT1) in human leukemias. 1992;6(5):405–9.
  12. Alberta JA, Springett GM, Rayburn H, et al. Role of the WT1 tumor suppressor in murine hematopoiesis. Blood. 2003;101(7):2570–4. doi: 10.1182/blood-2002-06-1656. DOI: https://doi.org/10.1182/blood-2002-06-1656
  13. Гиршова Л.Л., Будаева И.Г., Овсянникова Е.Г. и др. Прогностическое значение и корреляция динамики гиперэкспрессии гена WT1 и мутации гена NPM1 у пациентов с острым миелобластным лейкозом. Клиническая онкогематология. 2017;10(4):485–93. doi: 10.21320/2500-2139-2017-10-4-485-493.
  14. [Girshova LL, Budaeva IG, Ovsyannikova EG, et al. Prognostic Value and Correlation Between WT1 Overexpression and NPM1 Mutation in Patients with Acute Myeloblastic Leukemia. Clinical oncohematology. 2017;10(4):485–93. doi: 10.21320/2500-2139-2017-10-4-485-493. (In Russ)] DOI: https://doi.org/10.21320/2500-2139-2017-10-4-485-493
  15. Мамаев Н.Н., Гудожникова Я.В., Горбунова А.В. Гиперэкспрессия гена WT1при злокачественных опухолях системы крови: теоретические и клинические аспекты (обзор литературы). Клиническая онкогематология. 2016;9(3):257–64. doi: 10.21320/2500-2139-2016-9-3-257-264. DOI: https://doi.org/10.21320/2500-2139-2016-9-3-257-264
  16. [Mamaev NN, Gudozhnikova YaV, Gorbunova AV. WT1 Gene Overexpression in Oncohematological Disorders: Theoretical and Clinical Aspects (Literature Review). Clinical oncohematology. 2016;9(3):257–64. doi: 10.21320/2500-2139-2016-9-3-257-264. (In Russ)] DOI: https://doi.org/10.21320/2500-2139-2016-9-3-257-264
  17. Будаева И.Г., Гиршова Л.Л., Кузин С.О. и др. Прогностическое значение уровня гена WT1 у больных острыми миелоидными лейкозами с изолированной мутацией NPM1 и мутацией NPM1 c дополнительными молекулярными маркерами. Клиническая онкогематология. 2017;10(4):530–1. DOI: https://doi.org/10.21320/2500-2139-2017-10-4-485-493
  18. [Budaeva IG, Girshova LL, Kuzin SO, et al. Prognostic Value of WT1 Gene Level in Patients with Acute Myeloid Leukemia with Isolated NPM1 and NPM1 Mutation with Additional Molecular Markers. Clinical oncohematology. 2017;10(4):530–1. (In Russ)]
  19. Tamura H, Dan K, Yokose N, et al. Prognostic significance of WT1 mRNA and anti-WT1 antibody levels in peripheral blood in patients with myelodysplastic syndromes. Leuk Res. 2010;34(8):986–90. doi: 10.1016/j.leukres.2009.11.029. DOI: https://doi.org/10.1016/j.leukres.2009.11.029
  20. Gallo D, Nicoli P, Calabrese C, et al. The Wilms’ tumor (WT1) gene expression correlates with the International Prognostic Scoring System (IPSS) score in patients with myelofibrosis and it is a marker of response to therapy. Cancer Medicine. 2016;5(7):1650–3. doi: 10.1002/cam4.735. DOI: https://doi.org/10.1002/cam4.735
  21. Siordiya N, Lisina E, Butylin P, et al. Incidence of Elevated Expression of wt1 in Primary Myelofibrosis (pmf) and Postpv-, Postet Myelofibrosis and Its Dynamics during Ruxolitinib Treatment. 2016;128:5498. DOI: https://doi.org/10.1182/blood.V128.22.5498.5498
  22. Сиордия Н.Т., Булычева Е.Н., Холопова И.В. Частота встречаемости гиперэкспрессии WT1 у пациентов с миелоидными неоплазиями. Бюллетень Федерального Центра сердца, крови и эндокринологии им. В.А. Алмазова. 2012;6(17):116–20.
  23. [Siordiya NT, Bulycheva EN, Kholopova IV. WT1 overexpression rate in patents with myeloid neoplasm. Byulleten’ Federal’nogo Tsentra serdtsa, krovi i endokrinologii im. A. Almazova. 2012;6(17):116–20. (In Russ)]
  24. Cilloni D, Renneville A, Hermitte F, et al. Real-time quantitative polymerase chain reaction detection of minimal residual disease by standardized WT1 assay to enhance risk stratification in acute myeloid leukemia: A European Leukemia Net study. J Clin Oncol. 2009;27(31):5195–201. doi: 10.1200/jco.2009.22.4865. DOI: https://doi.org/10.1200/JCO.2009.22.4865
  25. Vizmanos JL, Ormazabal C, Larrayoz MJ, et al. JAK2 V617F mutation in classic chronic myeloproliferative diseases: a report on a series of 349 patients. Leukemia. 2006;20(3):534–5. doi: 10.1038/sj.leu.2404086. DOI: https://doi.org/10.1038/sj.leu.2404086
  26. Nangalia J, Massie CE, Baxter EJ, et al. Somatic CALR Mutations in Myeloproliferative Neoplasms with Nonmutated JAK2 N Engl J Med. 2013;369(25):2391–405. doi: 10.1056/NEJMoa1312542. DOI: https://doi.org/10.1056/NEJMoa1312542
  27. Beer PA, Campbell PJ, Scott LM, et al. MPL mutations in myeloproliferative disorders: analysis of the PT-1 cohort. 2008;112(1):141–9. doi: 10.1182/blood-2008-01-131664. DOI: https://doi.org/10.1182/blood-2008-01-131664
  28. Меликян А.Л., Суборцева И.Н., Судариков А.Б. и др. Клинические особенности эссенциальной тромбоцитемии и первичного миелофиброза в зависимости от молекулярных характеристик заболевания. Терапевтический архив. 2017;89(7):4–9. doi: 10.17116/terarkh20178974-9. DOI: https://doi.org/10.17116/terarkh20178974-9
  29. [Melikyan AL, Subortseva IN, Sudarikov AB, et al. Clinical features of essential thrombocythemia and primary myelofibrosis, depending on the molecular characteristics of disease. Terapevticheskii arkhiv. 2017;89(7):4–9. doi: 10.17116/terarkh20178974-9. (In Russ)] DOI: https://doi.org/10.17116/terarkh20178974-9
  30. Жернякова А.А., Мартынкевич И.С., Шуваев В.А. и др. Молекулярно-генетические маркеры и особенности течения эссенциальной тромбоцитемии. Клиническая онкогематология. 2017;10(3):402–8. doi: 10.21320/2500-2139-2017-10-3-402-408. DOI: https://doi.org/10.21320/2500-2139-2017-10-3-402-408
  31. [Zhernyakova AA, Martynkevich IS, Shuvaev VA, et al. Molecular Genetic Markers and Clinical Characteristics of Essential Thrombocythemia. Clinical oncohematology. 2017;10(3):402–8. doi: 10.21320/2500-2139-2017-10-3-402-408. (In Russ)] DOI: https://doi.org/10.21320/2500-2139-2017-10-3-402-408
  32. Лисина Е.Г., Сиордия Н.Т., Бутылин П.А. и др. Клинико-лабораторные особенности эссенциального тромбоцитоза и первичного миелофиброза в зависимости от мутационного статуса генов JAK2 и CALR1. Онкогематология. 2017;12(3):8–16.
  33. [Lisina EG, Siordiya NT, Butylin PA, et al. Clinical and laboratory features of essential thrombocytosis and primary myelofibrosis depending on JAK2 and CALR1 mutation status. 2017;12(3):8–16. (In Russ)]
  34. Delic S, Rose D, Kern W, et al. Application of an NGS-based 28-gene panel in myeloproliferative neoplasms reveals distinct mutation patterns in essential thrombocythaemia, primary myelofibrosis and polycythaemia vera. Br J Haematol. 2016;175(3):419–26. doi: 10.1111/bjh.14269. DOI: https://doi.org/10.1111/bjh.14269
  35. Tefferi A. Novel mutations and their functional and clinical relevance in myeloproliferative neoplasms: JAK2, MPL, TET2, ASXL1, CBL, IDH and IKZF1. Leukemia. 2010;24(6):1128–38. doi: 10.1038/leu2010.69. DOI: https://doi.org/10.1038/leu.2010.69
  36. Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016;127(20):2391–405. doi: 10.1182/blood-2016-03-643544. DOI: https://doi.org/10.1182/blood-2016-03-643544
  37. Меликян А.Л., Туркина А.Г., Ковригина А.М. и др. Клинические рекомендации по диагностике и терапии Ph-негативных миелопролиферативных заболеваний (истинная полицитемия, эссенциальная тромбоцитемия, первичный миелофиброз) (редакция 2016 г.). Гематология и трансфузиология. 2017;62(1, прил. 1):25–60.
  38. [Melikyan AL, Turkina AG, Kovrigina AM, et al. Clinical recommendations for diagnosis and therapy of Ph-negative myeloproliferative disorders (polycythemia vera, essential thrombocythemia, primary myelofibrosis) (edition 2016). Gematologiya i transfuziologiya. 2017;62(1, Suppl 1):25–60. (In Russ)]
  39. Bain BJ. Bone marrow biopsy morbidity: review of 2003. J Clin Pathol. 2005;58(4):406–8. doi: 10.1136/jcp.2004.022178. DOI: https://doi.org/10.1136/jcp.2004.022178
  40. Arora B, Sirhan S, Hoyer JD, et al. Peripheral blood CD34 count in myelofibrosis with myeloid metaplasia: a prospective evaluation of prognostic value in 94 patients. Br J Haematol. 2005;128(1):42–8. doi: 10.1111/j.1365-2141.2004.05290.x. DOI: https://doi.org/10.1111/j.1365-2141.2004.05280.x
  41. Barosi G, Viarengo G, Pecci A, et al. Diagnostic and clinical relevance of the number of circulating CD34+ cells in myelofibrosis with myeloidmetaplasia. Blood. 2001;98(12):3249–55. doi: 10.1182/blood.V98.12.3249. DOI: https://doi.org/10.1182/blood.V98.12.3249
  42. Xu M, Bruno E, Chao J, et al. Constitutive mobilization of CD34+ cells into the peripheral blood in idiopathic myelofibrosis may be due to the action of a number of proteases. Blood. 2005;105(11):4508–15. doi: 10.1182/blood-2004-08-3238. DOI: https://doi.org/10.1182/blood-2004-08-3238
  43. Забелина Т.С., Постриганева Т.И., Сайдали М.А. и др. Колониеобразующая способность клеток костного мозга и крови больных с различными формами лейкозов. Терапевтический архив. 1977;6:53–9.
  44. [Zabelina TS, Postriganeva TI, Saidali MA, et al. Bone marrow and blood cell colony-forming ability in patients with different leukemia types. Terapevticheskii arkhiv. 1977;6:53–9. (In Russ)]
  45. Harrison CN, Vannucchi AM, Kiladjian JJ, et al. Long-term findings from COMFORT-II, a phase 3 study of ruxolitinib vs best available therapy for myelofibrosis. Leukemia. 2016;30(8):1701–7. doi: 10.1038/leu.2016.148. DOI: https://doi.org/10.1038/leu.2016.148
  46. Verstovsek S, Gupta V, Jason R, et al. A Pooled Overall Survival (OS) Analysis of 5-Year Data from the COMFORT-I and COMFORT-II Trials of Ruxolitinib for the Treatment of Myelofibrosis (MF). 2016;128(22):3110. DOI: https://doi.org/10.1182/blood.V128.22.3110.3110
  47. Ионова Т.И., Анчукова Л.В., Виноградова О.Ю. и др. Качество жизни и спектр симптомов у больных миелофиброзом на фоне терапии: данные клинической практики. Гематология и трансфузиология. 2016;61(1):17–25.
  48. [Ionova TI, Anchukova LV, Vinogradova OYu, et al. Quality of life and symptoms in patients with myelofibrosis during the treatment: Data of clinical practice. Gematologiya i transfuziologiya. 2016;61(1):17–25. (In Russ)]
  49. Foltz L, Palumbo GA, Martino B, et al. Safety and Efficacy of Ruxolitinib for the Final Enrollment of JUMP: An Open-Label, Multicenter, Single-Arm, Expanded-Access Study in Patients with Myelofibrosis (n=2233). Blood. 2016;128(22):3107. DOI: https://doi.org/10.1182/blood.V128.22.3107.3107

Keywords:

WT1 gene, Ph-negative myeloproliferative disorders, myelofibrosis, polycythemia vera, essential thrombocythemia

License

Copyright (c) 2019 Clinical Oncohematology

Creative Commons License

This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.

Downloads

Download data is not yet available.
2019-3

Downloads

Published

01.07.2019

Issue

Vol. 12 No. 3 (2019)
MYELOID TUMORS

How to Cite

Lomaia E.G., Siordiya N.T., Lisina E.G., Senderova O.M., Silyutina A.A., Zaritskey A.Y. WT1 Gene Overexpression in Differential Diagnosis of Ph-negative Myeloproliferative Disorders. Clinical Oncohematology. Basic Research and Clinical Practice. 2019;12(3):297–302. doi:10.21320/2500-2139-2019-12-3-297-302.

Most read articles by the same author(s)

1 2 3 4 > >>