Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Acute Leukemias

The Fat1 cadherin is overexpressed and an independent prognostic factor for survival in paired diagnosis–relapse samples of precursor B-cell acute lymphoblastic leukemia

Leukemia volume 26, pages 918–926 (2012)Cite this article

Abstract

Improved survival of patients with acute lymphoblastic leukemia (ALL) has emerged from identifying new prognostic markers; however, 20% of children still suffer recurrence. Previously, the altered expression of Fat1 cadherin has been implicated in a number of solid tumors. In this report, in vitro analysis shows that Fat1 protein is expressed by a range of leukemia cell lines, but not by normal peripheral blood (PB) and bone marrow (BM) cells from healthy donors. In silico analysis of expression of array data from clinical leukemias found significant levels of Fat1 transcript in 11% of acute myeloid leukemia, 29% and 63% of ALL of B and T lineages, respectively, and little or no transcript present in normal PB or BM. Furthermore, in two independent studies of matched diagnosis–relapse of precursor B-cell (preB) ALL pediatric samples (n=32 and n=27), the level of Fat1 mRNA expression was prognostic at the time of diagnosis. High Fat1 mRNA expression was predictive of shorter relapse-free and overall survival, independent of other traditional prognostic markers, including white blood cell count, sex and age. The data presented demonstrate that Fat1 expression in preB-ALL has a role in the emergence of relapse and could provide a suitable therapeutic target in high-risk preB-ALL.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5

Similar content being viewed by others

Accession codes

Accessions

Gene Expression Omnibus

References

  1. Kawamata N, Ogawa S, Zimmermann M, Kato M, Sanada M, Hemminki K et al. Molecular allelokaryotyping of pediatric acute lymphoblastic leukemias by high-resolution single nucleotide polymorphism oligonucleotide genomic microarray. Blood 2008; 111: 776–784.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Mullighan CG, Goorha S, Radtke I, Miller CB, Coustan-Smith E, Dalton JD et al. Genome-wide analysis of genetic alterations in acute lymphoblastic leukaemia. Nature 2007; 446: 758–764.

    Article  CAS  PubMed  Google Scholar 

  3. Iacobucci I, Storlazzi CT, Cilloni D, Lonetti A, Ottaviani E, Soverini S et al. Identification and molecular characterization of recurrent genomic deletions on 7p12 in the IKZF1 gene in a large cohort of BCR-ABL1-positive acute lymphoblastic leukemia patients: on behalf of Gruppo Italiano Malattie Ematologiche dell’Adulto Acute Leukemia Working Party (GIMEMA AL WP). Blood 2009; 114: 2159–2167.

    Article  CAS  PubMed  Google Scholar 

  4. Kuiper RP, Schoenmakers EF, van Reijmersdal SV, Hehir-Kwa JY, van Kessel AG, van Leeuwen FN et al. High-resolution genomic profiling of childhood ALL reveals novel recurrent genetic lesions affecting pathways involved in lymphocyte differentiation and cell cycle progression. Leukemia 2007; 21: 1258–1266.

    Article  CAS  PubMed  Google Scholar 

  5. Strefford JC, Worley H, Barber K, Wright S, Stewart AR, Robinson HM et al. Genome complexity in acute lymphoblastic leukemia is revealed by array-based comparative genomic hybridization. Oncogene 2007; 26: 4306–4318.

    Article  CAS  PubMed  Google Scholar 

  6. Kuiper RP, Waanders E, van der Velden VH, van Reijmersdal SV, Venkatachalam R, Scheijen B et al. IKZF1 deletions predict relapse in uniformly treated pediatric precursor B-ALL. Leukemia 2010; 24: 1258–1264.

    Article  CAS  PubMed  Google Scholar 

  7. Borowitz MJ, Pullen DJ, Winick N, Martin PL, Bowman WP, Camitta B . Comparison of diagnostic and relapse flow cytometry phenotypes in childhood acute lymphoblastic leukemia: implications for residual disease detection: a report from the children's oncology group. Cytometry B Clin Cytom 2005; 68: 18–24.

    Article  PubMed  Google Scholar 

  8. Henderson MJ, Choi S, Beesley AH, Sutton R, Venn NC, Marshall GM et al. Mechanism of relapse in pediatric acute lymphoblastic leukemia. Cell Cycle 2008; 7: 1315–1320.

    Article  CAS  PubMed  Google Scholar 

  9. Mullighan CG, Phillips LA, Su X, Ma J, Miller CB, Shurtleff SA et al. Genomic analysis of the clonal origins of relapsed acute lymphoblastic leukemia. Science 2008; 322: 1377–1380.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Anderson K, Lutz C, van Delft FW, Bateman CM, Guo Y, Colman SM et al. Genetic variegation of clonal architecture and propagating cells in leukaemia. Nature 2011; 469: 356–361.

    Article  CAS  PubMed  Google Scholar 

  11. Notta F, Mullighan CG, Wang JC, Poeppl A, Doulatov S, Phillips LA et al. Evolution of human BCR-ABL1 lymphoblastic leukaemia-initiating cells. Nature 2011; 469: 362–367.

    Article  CAS  PubMed  Google Scholar 

  12. Collins-Underwood JR, Mullighan CG . Genomic profiling of high-risk acute lymphoblastic leukemia. Leukemia 2010; 24: 1676–1685.

    Article  CAS  PubMed  Google Scholar 

  13. Dunne J, Hanby AM, Poulsom R, Jones TA, Sheer D, Chin WG et al. Molecular cloning and tissue expression of FAT, the human homologue of the Drosophila fat gene that is located on chromosome 4q34-q35 and encodes a putative adhesion molecule. Genomics 1995; 30: 207–223.

    Article  CAS  PubMed  Google Scholar 

  14. Ponassi M, Jacques TS, Ciani L, ffrench Constant C . Expression of the rat homologue of the Drosophila fat tumour suppressor gene. Mech Dev 1999; 80: 207–212.

    Article  CAS  PubMed  Google Scholar 

  15. Cox B, Hadjantonakis AK, Collins JE, Magee AI . Cloning and expression throughout mouse development of mfat1, a homologue of the Drosophila tumour suppressor gene fat. Dev Dyn 2000; 217: 233–240.

    Article  CAS  PubMed  Google Scholar 

  16. Down M, Power M, Smith SI, Ralston K, Spanevello M, Burns GF et al. Cloning and expression of the large zebrafish protocadherin gene, Fat. Gene Expr Patterns 2005; 5: 483–490.

    Article  CAS  PubMed  Google Scholar 

  17. Settakorn J, Kaewpila N, Burns GF, Leong AS . FAT, E-cadherin, beta catenin, HER 2/neu, Ki67 immuno-expression, and histological grade in intrahepatic cholangiocarcinoma. J Clin Pathol 2005; 58: 1249–1254.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Kwaepila N, Burns G, Leong AS . Immunohistological localisation of human FAT1 (hFAT) protein in 326 breast cancers. Does this adhesion molecule have a role in pathogenesis? Pathology 2006; 38: 125–131.

    Article  CAS  PubMed  Google Scholar 

  19. Sadeqzadeh E, de Bock CE, Zhang XD, Shipman KL, Scott NM, Song C et al. Dual processing of Fat1 cadherin by human melanoma cells generates distinct protein products. J Biol Chem 2011; 286: 28181–28191.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Katoh Y, Katoh M . Comparative integromics on FAT1, FAT2, FAT3 and FAT4. Int J Mol Med 2006; 18: 523–528.

    CAS  PubMed  Google Scholar 

  21. Chetcuti A, Aktas S, Mackie N, Ulger C, Toruner G, Alkan M et al. Expression profiling reveals MSX1 and EphB2 expression correlates with the invasion capacity of Wilms tumors. Pediatr Blood Cancer 2011; 57: 950–957.

    Article  PubMed  Google Scholar 

  22. Novershtern N, Subramanian A, Lawton LN, Mak RH, Haining WN, McConkey ME et al. Densely interconnected transcriptional circuits control cell states in human hematopoiesis. Cell 2011; 144: 296–309.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Eckfeldt CE, Mendenhall EM, Flynn CM, Wang TF, Pickart MA, Grindle SM et al. Functional analysis of human hematopoietic stem cell gene expression using zebrafish. PLoS Biol 2005; 3: e254.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Valk PJ, Verhaak RG, Beijen MA, Erpelinck CA, Barjesteh van Waalwijk van Doorn-Khosrovani S, Boer JM et al. Prognostically useful gene-expression profiles in acute myeloid leukemia. N Engl J Med 2004; 350: 1617–1628.

    Article  CAS  PubMed  Google Scholar 

  25. Bhojwani D, Kang H, Moskowitz NP, Min DJ, Lee H, Potter JW et al. Biologic pathways associated with relapse in childhood acute lymphoblastic leukemia: a Children's Oncology Group study. Blood 2006; 108: 711–717.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Staal FJ, de Ridder D, Szczepanski T, Schonewille T, van der Linden EC, van Wering ER et al. Genome-wide expression analysis of paired diagnosis-relapse samples in ALL indicates involvement of pathways related to DNA replication, cell cycle and DNA repair, independent of immune phenotype. Leukemia 2010; 24: 491–499.

    Article  CAS  PubMed  Google Scholar 

  27. Nguyen K, Devidas M, Cheng SC, La M, Raetz EA, Carroll WL et al. Factors influencing survival after relapse from acute lymphoblastic leukemia: a Children's Oncology Group study. Leukemia 2008; 22: 2142–2150.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Smith M, Arthur D, Camitta B, Carroll AJ, Crist W, Gaynon P et al. Uniform approach to risk classification and treatment assignment for children with acute lymphoblastic leukemia. J Clin Oncol 1996; 14: 18–24.

    Article  CAS  PubMed  Google Scholar 

  29. Coustan-Smith E, Song G, Clark C, Key L, Liu P, Mehrpooya M et al. New markers for minimal residual disease detection in acute lymphoblastic leukemia. Blood 2011; 117: 6267–6276.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Beroukhim R, Mermel CH, Porter D, Wei G, Raychaudhuri S, Donovan J et al. The landscape of somatic copy-number alteration across human cancers. Nature 2010; 463: 899–905.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Maser RS, Choudhury B, Campbell PJ, Feng B, Wong KK, Protopopov A et al. Chromosomally unstable mouse tumours have genomic alterations similar to diverse human cancers. Nature 2007; 447: 966–971.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Neale G, Su X, Morton CL, Phelps D, Gorlick R, Lock RB et al. Molecular characterization of the pediatric preclinical testing panel. Clin Cancer Res 2008; 14: 4572–4583.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Staal FJ, van der Burg M, Wessels LF, Barendregt BH, Baert MR, van den Burg CM et al. DNA microarrays for comparison of gene expression profiles between diagnosis and relapse in precursor-B acute lymphoblastic leukemia: choice of technique and purification influence the identification of potential diagnostic markers. Leukemia 2003; 17: 1324–1332.

    Article  CAS  PubMed  Google Scholar 

  34. Greaves M . Cancer stem cells: back to Darwin? Semin Cancer Biol 2010; 20: 65–70.

    Article  PubMed  Google Scholar 

  35. 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; 10: 4874–4884.

    Article  Google Scholar 

  36. Hawkins ED, Russell SM . Upsides and downsides to polarity and asymmetric cell division in leukemia. Oncogene 2008; 27: 7003–7017.

    Article  CAS  PubMed  Google Scholar 

  37. Skouloudaki K, Puetz M, Simons M, Courbard JR, Boehlke C, Hartleben B et al. Scribble participates in Hippo signaling and is required for normal zebrafish pronephros development. Proc Natl Acad Sci U S A 2009; 106: 8579–8584.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Grusche FA, Richardson HE, Harvey KF . Upstream regulation of the hippo size control pathway. Curr Biol 2010; 20: R574–R582.

    Article  CAS  PubMed  Google Scholar 

  39. Varelas X, Miller BW, Sopko R, Song S, Gregorieff A, Fellouse FA et al. The Hippo pathway regulates Wnt/beta-catenin signaling. Dev Cell 2010; 18: 579–591.

    Article  CAS  PubMed  Google Scholar 

  40. Tanoue T, Takeichi M . Mammalian Fat1 cadherin regulates actin dynamics and cell-cell contact. J Cell Biol 2004; 165: 517–528.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Ge X, Wang X . Role of Wnt canonical pathway in hematological malignancies. J Hematol Oncol 2010; 3: 33.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Nygren MK, Dosen-Dahl G, Stubberud H, Walchli S, Munthe E, Rian E . beta-catenin is involved in N-cadherin-dependent adhesion, but not in canonical Wnt signaling in E2A-PBX1-positive B acute lymphoblastic leukemia cells. Exp Hematol 2009; 37: 225–233.

    Article  CAS  PubMed  Google Scholar 

  43. Den Boer ML, van Slegtenhorst M, De Menezes RX, Cheok MH, Buijs-Gladdines JG, Peters ST et al. A subtype of childhood acute lymphoblastic leukaemia with poor treatment outcome: a genome-wide classification study. Lancet Oncol 2009; 10: 125–134.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Li Z, Zhang W, Wu M, Zhu S, Gao C, Sun L et al. Gene expression-based classification and regulatory networks of pediatric acute lymphoblastic leukemia. Blood 2009; 114: 4486–4493.

    Article  CAS  PubMed  Google Scholar 

  45. Ross ME, Zhou X, Song G, Shurtleff SA, Girtman K, Williams WK et al. Classification of pediatric acute lymphoblastic leukemia by gene expression profiling. Blood 2003; 102: 2951–2959.

    Article  CAS  PubMed  Google Scholar 

  46. Yeoh EJ, Ross ME, Shurtleff SA, Williams WK, Patel D, Mahfouz R et al. Classification, subtype discovery, and prediction of outcome in pediatric acute lymphoblastic leukemia by gene expression profiling. Cancer Cell 2002; 1: 133–143.

    Article  CAS  PubMed  Google Scholar 

  47. Raimondi SC, Behm FG, Roberson PK, Williams DL, Pui CH, Crist WM et al. Cytogenetics of pre-B-cell acute lymphoblastic leukemia with emphasis on prognostic implications of the t(1;19). J Clin Oncol 1990; 8: 1380–1388.

    Article  CAS  PubMed  Google Scholar 

  48. Vey N, Thomas X, Picard C, Kovascovicz T, Charin C, Cayuela JM et al. Allogeneic stem cell transplantation improves the outcome of adults with t(1;19)/E2A-PBX1 and t(4;11)/MLL-AF4 positive B-cell acute lymphoblastic leukemia: results of the prospective multicenter LALA-94 study. Leukemia 2006; 20: 2155–2161.

    Article  CAS  PubMed  Google Scholar 

  49. Jeha S, Pei D, Raimondi SC, Onciu M, Campana D, Cheng C et al. Increased risk for CNS relapse in pre-B cell leukemia with the t(1;19)/TCF3-PBX1. Leukemia 2009; 23: 1406–1409.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Pui CH, Campana D, Pei D, Bowman WP, Sandlund JT, Kaste SC et al. Treating childhood acute lymphoblastic leukemia without cranial irradiation. N Engl J Med 2009; 360: 2730–2741.

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Ciani L, Patel A, Allen ND, ffrench-Constant C . Mice lacking the giant protocadherin mFAT1 exhibit renal slit junction abnormalities and a partially penetrant cyclopia and anophthalmia phenotype. Mol Cell Biol 2003; 23: 3575–3582.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Smith TG, Van Hateren N, Tickle C, Wilson SA . The expression of Fat-1 cadherin during chick limb development. Int J Dev Biol 2007; 51: 173–176.

    Article  CAS  PubMed  Google Scholar 

  53. Hou R, Liu L, Anees S, Hiroyasu S, Sibinga NE . The Fat1 cadherin integrates vascular smooth muscle cell growth and migration signals. J Cell Biol 2006; 173: 417–429.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We are grateful to Dheepa Bhojwani who made clinical outcome data available. We thank Professor Murray Norris for his comments and critical review of the manuscript. This work was supported by a project grant from the National Health and Medical Research Council, Australia (455531), Hunter Medical Research Institute (HMRI-09-23 kindly sponsored by Gallerie Fine Jewellery) and the Leukaemia Foundation Australia. RFT was awarded a career development fellowship by the Cancer Institute NSW. AA is in receipt of the Arrow Bone Marrow Transplant Foundation Scholarship.

Author information

Author notes

  1. C E de Bock and A Ardjmand: These authors contributed equally to this study.

Authors and Affiliations

  1. Cancer Research Unit, School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, New South Wales, Australia

    C E de Bock, A Ardjmand, S M Bone, D M Campbell, K L Shipman, G F Burns & R F Thorne

  2. Leukaemia Foundation of Queensland Research Unit, Queensland Institute of Medical Research, Brisbane, Queensland, Australia

    C E de Bock, T M Yeadon, M D Spanevello & A W Boyd

  3. Hunter Medical Research Institute, New Lambton Heights, New South Wales, Australia

    C E de Bock, A Ardjmand, S M Bone, D Johnstone, D M Campbell, K L Shipman, L F Lincz, G F Burns & R F Thorne

  4. Cancer Research Program, Garvan Institute of Medical Research, Sydney, New South Wales, Australia

    T J Molloy

  5. Centre for Bioinformatics, Biomarker Discovery and Information-Based Medicine, University of Newcastle, Callaghan, New South Wales, Australia

    D Johnstone

  6. Gene and Stem Cell Therapy Program, Centenary Institute, Newtown, New South Wales, Australia

    J Holst

  7. Tumour Bank, Children's Hospital at Westmead, Westmead, New South Wales, Australia

    G Nelmes & D R Catchpoole

  8. Hunter Haematology Research Group, Calvary Mater Newcastle Hospital, Waratah, New South Wales, Australia

    L F Lincz

Authors
  1. C E de Bock
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. A Ardjmand
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. T J Molloy
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. S M Bone
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. D Johnstone
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. D M Campbell
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. K L Shipman
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. T M Yeadon
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. J Holst
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. M D Spanevello
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. G Nelmes
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. D R Catchpoole
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. L F Lincz
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. A W Boyd
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. G F Burns
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. R F Thorne
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to R F Thorne.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies the paper on the Leukemia website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

de Bock, C., Ardjmand, A., Molloy, T. et al. The Fat1 cadherin is overexpressed and an independent prognostic factor for survival in paired diagnosis–relapse samples of precursor B-cell acute lymphoblastic leukemia. Leukemia 26, 918–926 (2012). https://doi.org/10.1038/leu.2011.319

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/leu.2011.319

Keywords

This article is cited by

Search

Advanced search

Quick links