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Prognostic role of DOK family adapters in acute myeloid leukemia


Acute myeloid leukemia (AML) is a genetically and clinically heterogeneous disease. Gene mutational and expressional profile can aid the identification of different prognostic subgroups. Downstream of tyrosine kinase (DOK) proteins are a multigenic family of adaptors; some of them are key negative regulators of immune cell signaling. However, the expression and clinical implication of DOK family in AML has rarely been investigated. A total of 155 AML patients with DOK family (DOK1-7) expression data from The Cancer Genome Atlas database were enrolled in the study. In patients who only received chemotherapy, those with high expressions of DOK4 or DOK5 had significantly shorter EFS and OS than patients with low expressions (all P < 0.001), whereas high DOK7 expressers had longer EFS and OS than the low expressers (all P < 0.05). In patients who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT), however, all DOK members had no impact on EFS and OS. Multivariate analysis confirmed that high DOK5 expression was an independent risk factor for EFS and OS in untransplanted patients (all P < 0.05). Our study suggests that in AML, high expressions of DOK4 and DOK5 are adverse prognostic factors, high DOK7 expression is a good prognostic factor, but their effects can be overcome by allo-HSCT.

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  1. 1.

    Döhner H, Weisdorf DJ, Bloomfield CD. Acute myeloid leukemia. N Engl J Med. 2015;373:1136–52.

  2. 2.

    Bullinger L, Döhner K, Döhner H. Genomics of acute myeloid leukemia diagnosis and pathways. J Clin Oncol. 2017;35:934–46.

  3. 3.

    Mardis ER, Ding L, Dooling DJ, Larson DE, McLellan MD, Chen K, et al. Recurring mutations found by sequencing an acute myeloid leukemia genome. N Engl J Med. 2009;361:1058–66.

  4. 4.

    Metzelder SK, Schroeder T, Lübbert M, Ditschkowski M, Götze K, Scholl S, et al. Long-term survival of sorafenib-treated FLT3-ITD-positive acute myeloid leukaemia patients relapsing after allogeneic stem cell transplantation. Eur J Cancer. 2017;86:233–9.

  5. 5.

    Lin N, Fu W, Zhao C, Li BX, Yan XJ, Li Y. Biologico-clinical significance of DNMT3A variants expression in acute myeloid leukemia. Biochem Biophys Res Commun. 2017;494:270–7.

  6. 6.

    Minetto P, Guolo F, Clavio M, Kunkl A, Colombo N, Carminati E, et al. A blastic plasmacytoid dendritic cell neoplasm-like phenotype identifies a subgroup of npm1-mutated acute myeloid leukemia patients with worse prognosis. Am J Hematol. 2018;93:E33–5.

  7. 7.

    Patel JP, Gönen M, Figueroa ME, Fernandez H, Sun ZX, Racevskis J, et al. Prognostic relevance of integrated genetic profiling in acute myeloid leukemia. N Engl J Med. 2012;366:1079–89.

  8. 8.

    Coppin E, De Grandis M, Pandolfi PP, Arcangeli ML, Aurrand-Lions M, Nunès JA. Dok1 and Dok2 proteins regulate cell cycle in hematopoietic stem and progenitor cells. J Immunol. 2016;196:4110–21.

  9. 9.

    Celis-Gutierrez J, Boyron M, Walzer T, Pandolfi PP, Jonjić S, Olive D, et al. Dok1 and Dok2 proteins regulate natural killer cell development and function. EMBO J. 2014;33:1928–40.

  10. 10.

    Mashima R, Hishida Y, Tezuka T, Yamanashi Y. The roles of Dok family adapters in immunoreceptor signaling. Immunol Rev. 2009;232:273–85.

  11. 11.

    Dong S, Corre B, Foulon E, Dufour E, Veillette A, Acuto O, et al. T cell receptor for antigen induces linker for activation of T cell-dependent activation of a negative signaling complex involving Dok-2, SHIP-1, and Grb-2. J Exp Med. 2006;203:2509–18.

  12. 12.

    Ott VL, Tamir I, Niki M, Pandolfi PP, Cambier JC. Downstream of kinase, p62(dok), is a mediator of Fc gamma IIB inhibition of Fc epsilon RI signaling. J Immunol. 2002;168:4430–9.

  13. 13.

    Coppin E, Gelsi-Boyer V, Morelli X, Cervera N, Murati A, Pandolfi PP, et al. Mutational analysis of the DOK2 haploinsufficient tumor suppressor gene in chronic myelomonocytic leukemia (CMML). Leukemia. 2015;29:500–2.

  14. 14.

    Mashima R, Honda K, Yang Y, Morita Y, Inoue A, Arimura S, et al. Mice lacking Dok-1, Dok-2, and Dok-3 succumb to aggressive histiocytic sarcoma. Lab Invest. 2010;90:1357–64.

  15. 15.

    He PF, Xu ZJ, Zhou JD, Li XX, Zhang W, Wu DH, et al. Methylation-associated DOK1 and DOK2 down-regulation: Potential biomarkers for predicting adverse prognosis in acute myeloid leukemia. J Cell Physiol. 2018;233:6604–14.

  16. 16.

    Heyn H, Carmona FJ, Gomez A, Ferreira HJ, Bell JT, Sayols S, et al. DNA methylation profiling in breast cancer discordant identical twins identifies DOK7 as novel epigenetic biomarker. Carcinogenesis. 2013;34:102–8.

  17. 17.

    Gupta V, Tallman MS, He W, Logan BR, Copelan E, Gale RP, et al. Comparable survival after HLA-well-matched unrelated or matched sibling donor transplantation for acute myeloid leukemia in first remission with unfavorable cytogenetics at diagnosis. Blood. 2010;116:1839–48.

  18. 18.

    Ley TJ, Miller C, Ding L, Raphael BJ, Mungall AJ, Robertson A, et al. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N Engl J Med. 2013;368:2059–74.

  19. 19.

    Al-Sarraf N, Reiff JN, Hinrichsen J, Mahmood S, Teh BT, McGovern E, et al. DOK4/IRS-5 expression is altered in clear cell renal cell carcinoma. Int J Cancer. 2007;121:992–8.

  20. 20.

    Hooker E, Baldwin C, Lemay S. New insights into Dok-4 PTB domain structure and function. Biochem Biophys Res Commun. 2012;427:67–72.

  21. 21.

    Masuda H, Zhang D, Bartholomeusz C, Doihara H, Hortobagyi GN, Ueno NT. Role of epidermal growth factor receptor in breast cancer. Breast Cancer Res Treat. 2012;136:331–45.

  22. 22.

    Morandi A, Plaza-Menacho I, Isacke CM. RET in breast cancer: functional and therapeutic implications. Trends Mol Med. 2011;17:149–57.

  23. 23.

    Shi L, Yue J, You Y, Yin B, Gong Y, Xu C, et al. Dok5 is substrate of TrkB and TrkC receptors and involved in neurotrophin induced MAPK activation. Cell Signal. 2006;18:1995–2003.

  24. 24.

    Jin W, Kim GM, Kim MS, Lim MH, Yun C, Jeong J, et al. TrkC plays an essential role in breast tumor growth and metastasis. Carcinogenesis. 2010;31:1939–47.

  25. 25.

    Bracken J, Ghanem T, Kasem A, Jiang WG, Mokbel K. Evidence for tumor suppressor function of DOK7 in human breast cancer. J Cancer Ther. 2014;5:67–73.

  26. 26.

    Yang SM, Li SY, Yu HB, Li JR, Sun LL. Repression of DOK7 mediated by DNMT3A promotes the proliferation and invasion of KYSE410 and TE-12 ESCC cells. Biomed Pharmacother. 2017;90:93–99.

  27. 27.

    Schoen MW, Woelich SK, Braun JT, Reddy DV, Fesler MJ, Petruska PJ, et al. Acute myeloid leukemia induction with cladribine: Outcomes by age and leukemia risk. Leuk Res. 2018;68:72–78.

  28. 28.

    de Jonge HJ, Valk PJ, de Bont ES, Schuringa JJ, Ossenkoppele G, Vellenga E, et al. Prognostic impact of white blood cell count in intermediate risk acute myeloid leukemia: relevance of mutated NPM1 and FLT3-ITD. Haematologica. 2011;96:1310–7.

  29. 29.

    Bacher U, Haferlach C, Alpermann T, Kern W, Schnittger S, Haferlach T. Comparison of genetic and clinical aspects in patients with acute myeloid leukemia and myelodysplastic syndromes all with more than 50% of bone marrow erythropoietic cells. Haematologica. 2011;96:1284–92.

  30. 30.

    Marcucci G, Metzeler KH, Schwind S, Becker H, Maharry K, Mrózek K, et al. Age-related prognostic impact of different types of DNMT3A mutations in adults with primary cytogenetically normal acute myeloid leukemia. J Clin Oncol. 2012;30:742–50.

  31. 31.

    Mendler JH, Maharry K, Radmacher MD, Mrózek K, Becker H, Metzeler KH, et al. RUNX1 mutations are associated with poor outcome in younger and older patients with cytogenetically normal acute myeloid leukemia and with distinct gene and MicroRNA expression signatures. J Clin Oncol. 2012;30:3109–18.

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This work was supported by grants from the National Natural Science Foundation of China (81500118, 61501519), the China Postdoctoral Science Foundation funded project (Project No. 2016M600443), Jiangsu Province Postdoctoral Science Foundation funded project (Project No. 1701184B), PLAGH project of Medical Big Data (Project No. 2016MBD-025).

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The authors declare that they have no conflict of interest.

Correspondence to Zhiheng Cheng or Lin Fu.

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