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Acute Leukemias

DNA methylation of membrane-bound tyrosine phosphatase genes in acute lymphoblastic leukaemia

Leukemia volume 28, pages 787–793 (2014)Cite this article

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Abstract

Aberrant DNA promoter methylation with associated gene silencing is a common epigenetic abnormality in acute lymphoblastic leukaemia (ALL) and is associated with poor survival. We have identified a family of transmembrane tyrosine phosphatase proteins as targets of hypermethylation in ALL and high-grade B cell lymphoma and demonstrated that this abnormal methylation correlates with transcript expression. PTPRG was methylated in 63% of ALL samples, PTPRK in 47%, PTPRM in 64% and PTPRO in 54% of cases, with most ALL samples containing methylation at multiple phosphatase loci. PTPRK promoter methylation was associated with a decreased overall survival in the cohort. Restoration of PTPRK transcript levels in leukaemia cells, where phosphatase transcript was silenced, reduced cell proliferation, inhibited colony formation and increased sensitivity to cytotoxic chemotherapy. These biological changes were associated with a reduction in levels of phosphorylated Erk1/2, Akt, STAT3 and STAT5 suggesting functional phosphatase activity after transcript re-expression. Methylation of the phosphatase promoters was reversible with decitabine and a histone deacetylase inhibitor, suggesting that PTPRK-mediated cell signalling pathways may be targeted with epigenetic therapies in lymphoid malignancy.

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References

  1. Garcia-Manero G, Daniel J, Smith TL, Kornblau SM, Lee MS, Kantarjian HM et al. DNA methylation of multiple promoter-associated CpG islands in adult acute lymphocytic leukemia. Clin Cancer Res 2002; 8: 2217–2224.

    CAS  PubMed  Google Scholar 

  2. Taylor KH, Pena-Hernandez KE, Davis JW, Arthur GL, Duff DJ, Shi H et al. Large-scale CpG methylation analysis identifies novel candidate genes and reveals methylation hotspots in acute lymphoblastic leukemia. Cancer Res 2007; 67: 2617–2625.

    Article  CAS  Google Scholar 

  3. Shen L, Toyota M, Kondo Y, Obata T, Daniel S, Pierce S et al. Aberrant DNA methylation of p57KIP2 identifies a cell-cycle regulatory pathway with prognostic impact in adult acute lymphocytic leukemia. Blood 2003; 101: 4131–4136.

    Article  CAS  Google Scholar 

  4. Bueso-Ramos C, Xu Y, McDonnell TJ, Brisbay S, Pierce S, Kantarjian H et al. Protein expression of a triad of frequently methylated genes, p73, p57Kip2 and p15, has prognostic value in adult acute lymphocytic leukemia independently of its methylation status. J Clin Oncol 2005; 23: 3932–3939.

    Article  CAS  Google Scholar 

  5. Canalli AA, Yang H, Jeha S, Hoshino K, Sanchez-Gonzalez B, Brandt M et al. Aberrant DNA methylation of a cell cycle regulatory pathway composed of P73, P15 and P57KIP2 is a rare event in children with acute lymphocytic leukemia. Leuk Res 2005; 29: 881–885.

    Article  CAS  Google Scholar 

  6. Alonso A, Sasin J, Bottini N, Friedberg I, Friedberg I, Osterman A et al. Protein tyrosine phosphatases in the human genome. Cell 2004; 117: 699–711.

    Article  CAS  Google Scholar 

  7. Aricescu AR, Siebold C, Choudhuri K, Chang VT, Lu W, Davis SJ et al. Structure of a tyrosine phosphatase adhesive interaction reveals a spacer-clamp mechanism. Science 2007; 317: 1217–1220.

    Article  CAS  Google Scholar 

  8. Gebbink MF, Zondaq GC, Koningstein GM, Feiken E, Wubbolts RW, Moolenaar WH . Cell surface expression of receptor protein tyrosine phosphatase RPTP μ is regulated by cell-cell contact. J Cell Biol 1995; 131: 251–260.

    Article  CAS  Google Scholar 

  9. Sap J, Jiang YP, Friedlander D, Grumet M, Schlessinger J . Receptor tyrosine phosphatase R-PTP-kappa mediates homophilic binding. Mol Cell Biol 1994; 14: 1–9.

    Article  CAS  Google Scholar 

  10. Wang SE, Wu FY, Shin I, Qu S, Arteaga CL . Transforming growth factor β (TGF-β)-Smad target gene protein tyrosine phosphatase receptor type kappa is required for TGF-β function. Mol Cell Biol 2005; 25: 4703–4715.

    Article  CAS  Google Scholar 

  11. Novellino L, De Filippo A, Deho P, Perrone F, Pilotti S, Parmiani G et al. PTPRK negatively regulates transcriptional activity of wild type and mutated oncogenic beta-catenin and affects membrane distribution of beta-catenin/E-cadherin complexes in cancer cells. Cell Signal 2008; 20: 872–883.

    Article  CAS  Google Scholar 

  12. Xu Y, Tan LJ, Grachtchouk V, Voorhees JJ, Fisher GJ . Receptor-type protein-tyrosine phosphatase-kappa regulates epidermal growth factor receptor function. J Biol Chem 2005; 280: 42694–42700.

    Article  CAS  Google Scholar 

  13. Xu Y, Baker D, Quan T, Baldassare JJ, Voorhees JJ, Fisher GJ . Receptor type protein tyrosine phosphatase-kappa mediates cross-talk between transforming growth factor-beta and epidermal growth factor receptor signaling pathways in human keratinocytes. Mol Biol Cell 2010; 21: 29–35.

    Article  CAS  Google Scholar 

  14. Sanchez-Morgan N, Kirsch KH, Trackman PC, Sonenshein GE . The lysyl oxidase propeptide interacts with the receptor-type protein tyrosine phosphatase kappa and inhibits β-catenin transcriptional activity in lung cancer cells. Mol Cell Biol 2011; 31: 3286–3297.

    Article  CAS  Google Scholar 

  15. Flavell JR, Baumforth KR, Wood VH, Davies GL, Wei W, Reynolds GM et al. Down-regulation of the TGF-beta target gene, PTPRK, by the Epstein-Barr virus encoded EBNA1 contributes to the growth and survival of Hodgkin lymphoma cells. Blood 2008; 111: 292–301.

    Article  CAS  Google Scholar 

  16. Kleppe M, Soulier J, Asnafi V, Mentens N, Hornakova T, Knoops L et al. PTPN2 negatively regulates oncogenic JAK1 in T-cell acute lymphoblastic leukemia. Blood 2011; 117: 7090–7098.

    Article  CAS  Google Scholar 

  17. Porcu M, Kleppe M, Gianfelici V, Geerdens E, De Keersmaecker K, Tartaglia M et al. Mutation of the receptor tyrosine phosphatase PTPRC (CD45) in T-cell acute lymphoblastic leukemia. Blood 2012; 119: 4476–4479.

    Article  CAS  Google Scholar 

  18. Kuang SQ, Tong WG, Yang H, Lin W, Lee MK, Fang ZH et al. Genome-wide identification of aberrantly methylated promoter associated CpG islands in acute lymphocytic leukemia. Leukemia 2008; 22: 1529–1538.

    Article  CAS  Google Scholar 

  19. Shu J, Jelinek J, Chang H, Shen L, Qin T, Chung W et al. Silencing of bidirectional promoters by DNA methylation in tumorigenesis. Cancer Res 2006; 66: 5077–5084.

    Article  CAS  Google Scholar 

  20. Tong WG, Wierda WG, Lin E, Kuang SQ, Bekele BN, Estrov Z et al. Genome-wide DNA methylation profiling of chronic lymphocytic leukemia allows identification of epigenetically repressed molecular pathways with clinical impact. Epigenetics 2010; 5: 499–508.

    Article  CAS  Google Scholar 

  21. Motiwala T, Majumder S, Kutay H, Smith DS, Neuberg DS, Lucas DM et al. Methylation and silencing of protein tyrosine phosphatase receptor type O in chronic lymphocytic leukemia. Clin Cancer Res 2007; 13: 3174–3181.

    Article  CAS  Google Scholar 

  22. Godfrey R, Arora D, Bauer R, Stopp S, Müller JP, Heinrich T et al. Cell transformation by FLT3 ITD in acute myeloid leukemia involves oxidative inactivation of the tumor suppressor protein-tyrosine phosphatase DEP-1/ PTPRJ. Blood 2012; 119: 4499–4511.

    Article  CAS  Google Scholar 

  23. Maksumova L, Wang Y, Wong NK, Le HT, Pallen CJ, Johnson P . Differential function of PTPalpha and PTPalpha Y789F in T cells and regulation of PTPalpha phosphorylation at Tyr-789 by CD45. J Biol Chem 2007; 282: 20925–20932.

    Article  CAS  Google Scholar 

  24. Wang B, Kishihara K, Zhang D, Hara H, Nomoto K . Molecular cloning and characterization of a novel human receptor protein tyrosine phophatase gene, hPTP-J: down-regulation of gene expression by PMA and calcium ionophore in Jurkat T lymphoma cells. Biochem Biophys Res Commun 1997; 231: 77–81.

    Article  CAS  Google Scholar 

  25. Tartaglia M, Niemeyer CM, Fragale A, Song X, Buechner J, Jung A et al. Somatic mutations in PTPN11 in juvenile myelomonocytic leukemia, myelodysplastic syndromes and acute myeloid leukemia. Nat Genet 2003; 34: 148–150.

    Article  CAS  Google Scholar 

  26. Kuang SQ, Bai H, Fang ZH, Lopez G, Yang H, Tong W et al. Aberrant DNA methylation and epigenetic inactivation of Eph receptor tyrosine kinases and ephrin ligands in acute lymphoblastic leukemia. Blood 2010; 115: 2412–2419.

    Article  CAS  Google Scholar 

  27. Gutierrez MI, Siraj AK, Bhargava M, Ozbek U, Banavali S, Chaudhary MA et al. Concurrent methylation of multiple genes in childhood ALL: correlation with phenotype and molecular subgroup. Leukemia 2003; 17: 1845–1850.

    Article  CAS  Google Scholar 

  28. Hogan LE, Meyer JA, Yang J, Wang J, Wong N, Yang W et al. Intergrated genomic analysis of relapsed childhood acute lymphoblastic leukemia reveals therapeutic strategies. Blood 2011; 118: 5218–5226.

    Article  CAS  Google Scholar 

  29. Bhatla T, Wang J, Morrison DJ, Raetz EA, Burke MJ, Brown P et al. Epigenetic reprogramming reverses the relapse-specific gene expression signature and restores chemosensitivity in childhood B-lymphoblastic leukemia. Blood 2012; 119: 5201–5210.

    Article  CAS  Google Scholar 

  30. Motiwala T, Majumder S, Ghoshal K, Kutay H, Datta J, Roy S et al. PTPROt inactivates the oncogenic fusion protein BCR/ABL and suppresses transformation of K562 cells. J Biol Chem 2009; 284: 455–464.

    Article  CAS  Google Scholar 

  31. Harvey RC, Mullighan CG, Wang X, Dobbin KK, Davidson GS, Bedrick EJ et al. Identification of novel cluster groups in pediatric high-risk B-precursor acute lymphoblastic leukemia with gene expression profiling: correlation with genome-wide DNA copy number alterations, clinical characteristics, and outcome. Blood 2010; 116: 4874–4884.

    Article  CAS  Google Scholar 

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Acknowledgements

WSS was supported by a Cancer Institute NSW International Clinical and Research Fellowship.

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Authors and Affiliations

  1. Department of Haematology, Royal North Shore Hospital, Pathology North, Sydney, Australia

    W S Stevenson, Q Chen, N Singh, M Koleth & T Kennedy

  2. Northern Blood Research Centre, Kolling Institute of Medical Research, University of Sydney, Sydney, Australia

    W S Stevenson, O G Best, A Przybylla & Q Chen

  3. Department of Leukemia, University of Texas, MD Anderson Cancer Center, Houston, TX, USA

    S Pierce, W Tong, S-Q Kuang & G Garcia-Manero

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  1. W S Stevenson
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Correspondence to W S Stevenson.

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Stevenson, W., Best, O., Przybylla, A. et al. DNA methylation of membrane-bound tyrosine phosphatase genes in acute lymphoblastic leukaemia. Leukemia 28, 787–793 (2014). https://doi.org/10.1038/leu.2013.270

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  • DOI: https://doi.org/10.1038/leu.2013.270

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