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Overexpressed WT1 exhibits a specific immunophenotype in intermediate and poor cytogenetic risk acute myeloid leukemia

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Abstract

Many studies have confirmed that overexpressed WT1 exists in leukemic cells, especially in AML. However, the immunophenotypic features of this sort of leukemic cells remain to be unclarified. We retrospectively analyzed the immunophenotype of 283 newly diagnosed AML patients with intermediated and poor cytogenetic risk to evaluate the correlation between phenotype and WT1 overexpression. EVI1 transcripts, KMT2A-PTD, FLT3-ITD, and NPM1 mutations were simultaneously assessed. Our results revealed that overexpressed WT1 was significantly associated with the expression of CD117, CD13, and CD123. Besides, leukemic cells with WT1 overexpression also lacked lymphoid and myeloid differentiation-related markers. FAB subtype M2 patients had higher WT1 levels, compared with other FAB subtype. Multivariate analysis was proved that NPM1 mutation, M2 subtype, and the expression of CD123 were independently associated with WT1 overexpression. These indicated that AML with overexpressed WT1 was proliferated and blocked in the early stage of AML development. It presumably provided some clues to detect overexpressed WT1 cells via multiparameter flow cytometry. CD123-targeted drugs might become one of the alternative treatments for patients with WT1 overexpression.

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References

  1. Yang L, Han Y, Suarez Saiz F, Minden MD (2007) A tumor suppressor and oncogene: the WT1 story. Leukemia 21(5):868–876. https://doi.org/10.1038/sj.leu.2404624

    Article  CAS  PubMed  Google Scholar 

  2. Inoue K, Ogawa H, Sonoda Y, Kimura T, Sakabe H, Oka Y, Miyake S, Tamaki H, Oji Y, Yamagami T, Tatekawa T, Soma T, Kishimoto T, Sugiyama H (1997) Aberrant overexpression of the Wilms tumor gene (WT1) in human leukemia. Blood 89(4):1405–1412

    Article  CAS  Google Scholar 

  3. Hidaka D, Onozawa M, Hashiguchi J, Miyashita N, Kasahara K, Fujisawa S, Hayase E, Okada K, Shiratori S, Goto H, Sugita J, Nakagawa M, Hashimoto D, Kahata K, Endo T, Yamamoto S, Tsutsumi Y, Haseyama Y, Nagashima T, Mori A, Ota S, Sakai H, Ishihara T, Imai K, Miyagishima T, Kakinoki Y, Kurosawa M, Kobayashi H, Iwasaki H, Shimizu C, Kondo T, Teshima T (2018) Wilms tumor 1 expression at diagnosis correlates with genetic abnormalities and polymorphism but is not independently prognostic in acute myelogenous leukemia: a Hokkaido leukemia net study. Clin Lymphoma Myeloma Leuk 18(11):e469–e479. https://doi.org/10.1016/j.clml.2018.07.291

    Article  PubMed  Google Scholar 

  4. Cilloni D, Renneville A, Hermitte F, Hills RK, Daly S, Jovanovic JV, Gottardi E, Fava M, Schnittger S, Weiss T, Izzo B, Nomdedeu J, van der Heijden A, van der Reijden BA, Jansen JH, van der Velden VH, Ommen H, Preudhomme C, Saglio G, Grimwade D (2009) 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 LeukemiaNet study. J Clin Oncol 27(31):5195–5201. https://doi.org/10.1200/JCO.2009.22.4865

    Article  CAS  PubMed  Google Scholar 

  5. Paietta E, Wiernik PH, Andersen J, Bennett J, Yunis J (1993) Acute myeloid leukemia M4 with inv(16) (p13q22) exhibits a specific immunophenotype with CD2 expression. Blood 82(8):2595

    Article  CAS  Google Scholar 

  6. Andrieu V, Radford-Weiss I, Troussard X, Chane C, Valensi F, Guesnu M, Haddad E, Viguier F, Dreyfus F, Varet B, Flandrin G, Macintyre E (1996) Molecular detection of t(8;21)/AML1-ETO in AML M1/M2: correlation with cytogenetics, morphology and immunophenotype. Br J Haematol 92(4):855–865

    Article  CAS  Google Scholar 

  7. Gorczyca W (2012) Acute promyelocytic leukemia: four distinct patterns by flow cytometry immunophenotyping. Pol J Pathol 63(1):8–17

    PubMed  Google Scholar 

  8. (2019) National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology. Acute Myeloid Leukemia. Version 3.2018 (URL: https://www.nccn.org)

  9. Zhou Y, Wood BL (2017) Methods of detection of measurable residual disease in AML. Curr Hematol Malig Rep 12(6):557–567. https://doi.org/10.1007/s11899-017-0419-5

    Article  PubMed  Google Scholar 

  10. Ruan GR, Li JL, Qin YZ, Li LD, Xie M, Chang Y, Zhang Y, Liu YR, Jiang B, Chen SS (2009) Nucleophosmin mutations in Chinese adults with acute myelogenous leukemia. Ann Hematol 88(2):159–166. https://doi.org/10.1007/s00277-008-0591-8

    Article  CAS  PubMed  Google Scholar 

  11. Yazhen Q, Honghu Z, Bin J, Jinlan L, Xijing L, Lingdi L, Guorui R, Yanrong L, Shanshan C, Xiaojun H (2009) Expression patterns of WT1 and PRAME in acute myeloid leukemia patients and their usefulness for monitoring minimal residual disease. Leuk Res 33(3):384–390. https://doi.org/10.1016/j.leukres.2008.08.026

    Article  CAS  Google Scholar 

  12. Qin Y-Z, Zhao T, Zhu H-H, Wang J, Jia J-S, Lai Y-Y, Zhao X-S, Shi H-X, Liu Y-R, Jiang H, Huang X-J, Jiang Q (2018) High EVI1 expression predicts poor outcomes in adult acute myeloid leukemia patients with intermediate cytogenetic risk receiving chemotherapy. Med Sci Monit 24:758–767. https://doi.org/10.12659/msm.905903

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Liu YR, Zhu HH, Ruan GR, Qin YZ, Shi HX, Lai YY, Chang Y, Wang YZ, Lu D, Hao L, Li JL, Li LD, Jiang B, Huang XJ (2013) NPM1-mutated acute myeloid leukemia of monocytic or myeloid origin exhibit distinct immunophenotypes. Leuk Res 37(7):737–741. https://doi.org/10.1016/j.leukres.2013.03.009

    Article  CAS  PubMed  Google Scholar 

  14. Syampurnawati M, Tatsumi E, Ardianto B, Takenokuchi M, Nakamachi Y, Kawano S, Kumagai S, Saigo K, Matsui T, Takahashi T, Nagai K, Gunadi, Nishio H, Yabe H, Kondo S, Hayashi Y (2008) DR negativity is a distinctive feature of M1/M2 AML cases with NPM1 mutation. Leuk Res 32(7):1141–1143. https://doi.org/10.1016/j.leukres.2007.11.017

    Article  CAS  PubMed  Google Scholar 

  15. Chen W, Konoplev S, Medeiros LJ, Koeppen H, Leventaki V, Vadhan-Raj S, Jones D, Kantarjian HM, Falini B, Bueso-Ramos CE (2009) Cuplike nuclei (prominent nuclear invaginations) in acute myeloid leukemia are highly associated with FLT3 internal tandem duplication and NPM1 mutation. Cancer 115(23):5481–5489. https://doi.org/10.1002/cncr.24610

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Weisser M, Kern W, Rauhut S, Schoch C, Hiddemann W, Haferlach T, Schnittger S (2005) Prognostic impact of RT-PCR-based quantification of WT1 gene expression during MRD monitoring of acute myeloid leukemia. Leukemia 19(8):1416–1423. https://doi.org/10.1038/sj.leu.2403809

    Article  CAS  PubMed  Google Scholar 

  17. Trka J, Kalinova M, Hrusak O, Zuna J, Krejci O, Madzo J, Sedlacek P, Vavra V, Michalova K, Jarosova M, Stary J (2002) Real-time quantitative PCR detection of WT1 gene expression in children with AML: prognostic significance, correlation with disease status and residual disease detection by flow cytometry. Leukemia 16(7):1381–1389. https://doi.org/10.1038/sj.leu.2402512

    Article  CAS  PubMed  Google Scholar 

  18. van Dijk JP, Knops GH, van de Locht LTF, Menke AL, Jansen JH, Mensink EJBM, Raymakers RAP, de Witte T (2002) Abnormal WT1 expression in the CD34-negative compartment in myelodysplastic bone marrow. Br J Haematol 118:1027–1033

    Article  Google Scholar 

  19. Mason EF, Kuo FC, Hasserjian RP, Seegmiller AC, Pozdnyakova O (2018) A distinct immunophenotype identifies a subset of NPM1-mutated AML with TET2 or IDH1/2 mutations and improved outcome. Am J Hematol 93(4):504–510. https://doi.org/10.1002/ajh.25018

    Article  CAS  PubMed  Google Scholar 

  20. Taussig DC, Vargaftig J, Miraki-Moud F, Griessinger E, Sharrock K, Luke T, Lillington D, Oakervee H, Cavenagh J, Agrawal SG, Lister TA, Gribben JG, Bonnet D (2010) Leukemia-initiating cells from some acute myeloid leukemia patients with mutated nucleophosmin reside in the CD34(-) fraction. Blood 115(10):1976–1984. https://doi.org/10.1182/blood-2009-02-206565

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Papaemmanuil E, Gerstung M, Bullinger L, Gaidzik VI, Paschka P, Roberts ND, Potter NE, Heuser M, Thol F, Bolli N, Gundem G, Van Loo P, Martincorena I, Ganly P, Mudie L, McLaren S, O’Meara S, Raine K, Jones DR, Teague JW, Butler AP, Greaves MF, Ganser A, Dohner K, Schlenk RF, Dohner H, Campbell PJ (2016) Genomic classification and prognosis in acute myeloid leukemia. N Engl J Med 374(23):2209–2221. https://doi.org/10.1056/NEJMoa1516192

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Hosen N, Shirakata T, Nishida S, Yanagihara M, Tsuboi A, Kawakami M, Oji Y, Oka Y, Okabe M, Tan B, Sugiyama H, Weissman IL (2007) The Wilms’ tumor gene WT1-GFP knock-in mouse reveals the dynamic regulation of WT1 expression in normal and leukemic hematopoiesis. Leukemia 21(8):1783–1791. https://doi.org/10.1038/sj.leu.2404752

    Article  CAS  PubMed  Google Scholar 

  23. Bras AE, de Haas V, van Stigt A, Jongen-Lavrencic M, Beverloo HB, Te Marvelde JG, Zwaan CM, van Dongen JJM, Leusen JHW, van der Velden VHJ (2019) CD123 expression levels in 846 acute leukemia patients based on standardized immunophenotyping. Cytometry B Clin Cytom 96(2):134–142. https://doi.org/10.1002/cyto.b.21745

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

The authors thank Wei-Hua Shi, Lin-Lin He, Le Hao, and Jing Wu for their assistance.

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Authors and Affiliations

  1. Department of Clinical Laboratory, Shanghai General Hospital, Shanghai, China

    Xiao-Rui Wang

  2. Department of Hematology, Peking University People’s Hospital, Peking University Institute of Hematology, No. 11 Xizhimen South St, Beijing, 100044, China

    Xiao-Rui Wang, Yan Chang, Xiao-Ying Yuan, Ya-Zhe Wang, Ya-Zhen Qin, Guo-Rui Ruan, Yue-Yun Lai & Yan-Rong Liu

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  1. Xiao-Rui Wang
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  2. Yan Chang
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  3. Xiao-Ying Yuan
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Contributions

Xiao-Rui Wang and Yan-Rong Liu designed, wrote, and interpreted data. Yan Chang, Xiao-Ying Yuan, and Ya-Zhe Wang performed experiments and provided technical support. Ya-Zhen Qin, Guo-Rui Ruan, and Yue-Yun Lai performed experiments and analyzed data. All authors approved the manuscript. Yan-Rong Liu supervised the study.

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Correspondence to Yan-Rong Liu.

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All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (the Ethics Committee of Peking University People’s Hospital) and with the Helsinki Declaration of 1975, as revised in 2008. Since this is a retrospective study, formal informed consent is not required.

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The authors declare that they have no conflict of interest.

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Wang, XR., Chang, Y., Yuan, XY. et al. Overexpressed WT1 exhibits a specific immunophenotype in intermediate and poor cytogenetic risk acute myeloid leukemia. Ann Hematol 99, 215–221 (2020). https://doi.org/10.1007/s00277-019-03808-6

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  • DOI: https://doi.org/10.1007/s00277-019-03808-6

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