Skip to main content

Advertisement

SpringerLink
Log in

Differential gene expression in acute lymphoblastic leukemia cells surviving allogeneic transplant

  • Original Article
  • Published:
Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Abstract

The effectiveness of allogeneic graft-versus-leukemia (GVL) activity in control of acute lymphoblastic leukemia is generally regarded as poor. One possible factor is dynamic adaptation of the leukemia cell to the allogeneic environment. This work tested the hypothesis that the pattern of gene expression in acute lymphoblastic leukemia cells in an allogeneic environment would differ from that in a non-allogeneic environment. Expression microarray studies were performed in murine B lineage acute lymphoblastic leukemia cells recovered from mice that had undergone allogeneic MHC-matched but minor histocompatibility antigen mismatched transplants. A limited number of genes were found to be differentially expressed in ALL cells surviving in the allogeneic environment. Functional analysis demonstrated that genes related to immune processes, antigen presentation, ubiquitination and GTPase function were significantly enriched. Several genes with known immune activities potentially relevant to leukemia survival (Ly6a/Sca-1, TRAIL and H2-T23) were examined in independent validation experiments. Increased expression in vivo in allogeneic hosts was observed, and could be mimicked in vitro with soluble supernatants of mixed lymphocyte reactions or interferon-gamma. The changes in gene expression were reversible when the leukemia cells were removed from the allogeneic environment. These findings suggest that acute lymphoblastic leukemia cells respond to cytokines present after allogeneic transplantation and that these changes may reduce the effectiveness of GVL activity.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Dahlke J, Kroger N, Zabelina T, Ayuk F, Fehse N, Wolschke C, Waschke O, Schieder H, Renges H, Kruger W, Kruell A, Hinke A, Erttmann R, Kabisch H, Zander AR (2006) Comparable results in patients with acute lymphoblastic leukemia after related and unrelated stem cell transplantation. Bone Marrow Transplant 37:155–163

    Article  CAS  PubMed  Google Scholar 

  2. Woolfrey AE, Anasetti C, Storer B, Doney K, Milner LA, Sievers EL, Carpenter P, Martin P, Petersdorf E, Appelbaum FR, Hansen JA, Sanders JE (2002) Factors associated with outcome after unrelated marrow transplantation for treatment of acute lymphoblastic leukemia in children. Blood 99:2002–2008

    Article  CAS  PubMed  Google Scholar 

  3. Munoz A, Diaz-Heredia C, Diaz MA, Badell I, Verdeguer A, Martinez A, Gomez P, Perez-Hurtado JM, Bureo E, Fernandez-Delgado R, Gonzalez-Valentin ME, Maldonado MS (2008) Allogeneic hemopoietic stem cell transplantation for childhood acute lymphoblastic leukemia in second complete remission-similar outcomes after matched related and unrelated donor transplant: a study of the Spanish Working Party for Blood and Marrow Transplantation in Children (Getmon). Pediatr Hematol Oncol 25:245–259

    Article  CAS  PubMed  Google Scholar 

  4. Bhojwani D, Kang H, Moskowitz NP, Min DJ, Lee H, Potter JW, Davidson G, Willman CL, Borowitz MJ, Belitskaya-Levy I, Hunger SP, Raetz EA, Carroll WL (2006) Biologic pathways associated with relapse in childhood acute lymphoblastic leukemia: a Children’s Oncology Group study. Blood 108:711–717

    Article  CAS  PubMed  Google Scholar 

  5. Anderson LDMS, Mann S, Savary CA, Mullen CA (2000) Pretransplant tumor antigen-specific immunization of allogeneic bone marrow transplant donors enhances graft-versus-host disease. Cancer Res 60:5797–5802

    CAS  PubMed  Google Scholar 

  6. Bacher U, Kohlmann A, Haferlach T (2009) Current status of gene expression profiling in the diagnosis and management of acute leukaemia. Br J Haematol 145:555–568

    Article  CAS  PubMed  Google Scholar 

  7. Yang JJ, Bhojwani D, Yang W, Cai X, Stocco G, Crews K, Wang J, Morrison D, Devidas M, Hunger SP, Willman CL, Raetz EA, Pui CH, Evans WE, Relling MV, Carroll WL (2008) Genome-wide copy number profiling reveals molecular evolution from diagnosis to relapse in childhood acute lymphoblastic leukemia. Blood 112:4178–4183

    Article  CAS  PubMed  Google Scholar 

  8. Zembutsu H, Yanada M, Hishida A, Katagiri T, Tsuruo T, Sugiura I, Takeuchi J, Usui N, Naoe T, Nakamura Y, Ohno R (2007) Prediction of risk of disease recurrence by genome-wide cDNA microarray analysis in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia treated with imatinib-combined chemotherapy. Int J Oncol 31:313–322

    CAS  PubMed  Google Scholar 

  9. Iacobucci I, Lonetti A, Messa F, Cilloni D, Arruga F, Ottaviani E, Paolini S, Papayannidis C, Piccaluga PP, Giannoulia P, Soverini S, Amabile M, Poerio A, Saglio G, Pane F, Berton G, Baruzzi A, Vitale A, Chiaretti S, Perini G, Foa R, Baccarani M, Martinelli G (2008) Expression of spliced oncogenic Ikaros isoforms in Philadelphia-positive acute lymphoblastic leukemia patients treated with tyrosine kinase inhibitors: implications for a new mechanism of resistance. Blood 112:3847–3855

    Article  CAS  PubMed  Google Scholar 

  10. Young FM, Campbell A, Emo KL, Jansson J, Wang P-Y, Jordan CT, Mullen CA (2008) High-risk acute lymphoblastic leukemia cells with bcr-abl and INK4A/ARF mutations retain susceptibility to alloreactive T cells. Biol Blood Marrow Transplant 14:622–630

    Article  CAS  PubMed  Google Scholar 

  11. Mori S, El-Baki H, Mullen CA (2003) An analysis of immunodominance among minor histocompatibility antigens in allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant 31:865–875

    Article  CAS  PubMed  Google Scholar 

  12. Anderson LJ, Petropoulos D, Everse LA, Mullen CA (1999) Enhancement of graft-versus-tumor activity and graft-versus-host disease by pretransplant immunization of allogeneic bone marrow donors with a recipient-derived tumor cell vaccine. Cancer Res 59:1525–1530

    CAS  PubMed  Google Scholar 

  13. Li C, Wong WH (2001) Model-based analysis of oligonucleotide arrays: expression index computation and outlier detection. Proc Natl Acad Sci USA 98:31–36

    Article  CAS  PubMed  Google Scholar 

  14. Gentleman R, Carey VJ, Huber W, Irizarry RA, Dudroit S (2005) Bioinformatics and computational biology solutions using R and bioconductor. Springer, New York

    Book  Google Scholar 

  15. Norris AW, Kahn CR (2006) Analysis of gene expression in pathophysiological states: balancing false discovery and false negative rates. Proc Natl Acad Sci USA 103:649–653

    Article  CAS  PubMed  Google Scholar 

  16. Huang DW, Sherman BT, Lempicki RA (2009) Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc 4:44–57

    Article  CAS  Google Scholar 

  17. Bhattacharjee A, Richards WG, Staunton J, Li C, Monti S, Vasa P, Ladd C, Beheshti J, Bueno R, Gillette M, Loda M, Weber G, Mark EJ, Lander ES, Wong W, Johnson BE, Golub TR, Sugarbaker DJ, Meyerson M (2001) Classification of human lung carcinomas by mRNA expression profiling reveals distinct adenocarcinoma subclasses. Proc Natl Acad Sci USA 98:13790–13795

    Article  CAS  PubMed  Google Scholar 

  18. Cikos S, Bukovska A, Koppel J (2007) Relative quantification of mRNA: comparison of methods currently used for real-time PCR data analysis. BMC Mol Biol 8:113

    Article  PubMed  Google Scholar 

  19. Henderson SC, Kamdar MM, Bamezai A (2002) Ly-6A.2 expression regulates antigen-specific CD4+ T cell proliferation and cytokine production. J Immunol 168:118–126

    CAS  PubMed  Google Scholar 

  20. van de Rijn M, Heimfeld S, Spangrude GJ, Weissman IL (1989) Mouse hematopoietic stem-cell antigen Sca-1 is a member of the Ly-6 antigen family. Proc Natl Acad Sci USA 86:4634–4638

    Article  PubMed  Google Scholar 

  21. Lu L, Ikizawa K, Hu D, Werneck MB, Wucherpfennig KW, Cantor H (2007) Regulation of activated CD4+ T cells by NK cells via the Qa-1-NKG2A inhibitory pathway. Immunity 26:593–604

    Article  CAS  PubMed  Google Scholar 

  22. Ashkenazi A, Holland P, Eckhardt SG (2008) Ligand-based targeting of apoptosis in cancer: the potential of recombinant human apoptosis ligand 2/Tumor necrosis factor-related apoptosis-inducing ligand (rhApo2L/TRAIL). J Clin Oncol 26:3621–3630

    Article  CAS  PubMed  Google Scholar 

  23. Fakler M, Loeder S, Vogler M, Schneider K, Jeremias I, Debatin KM, Fulda S (2009) Small molecule XIAP inhibitors cooperate with TRAIL to induce apoptosis in childhood acute leukemia cells and overcome Bcl-2-mediated resistance. Blood 113:1710–1722

    Article  CAS  PubMed  Google Scholar 

  24. Uthaiah RC, Praefcke GJ, Howard JC, Herrmann C (2003) IIGP1, an interferon-gamma-inducible 47-kDa GTPase of the mouse, showing cooperative enzymatic activity and GTP-dependent multimerization. J Biol Chem 278:29336–29343

    Article  CAS  PubMed  Google Scholar 

  25. Boehm U, Guethlein L, Klamp T, Ozbek K, Schaub A, Futterer A, Pfeffer K, Howard JC (1998) Two families of GTPases dominate the complex cellular response to IFN-gamma. J Immunol 161:6715–6723

    CAS  PubMed  Google Scholar 

  26. Degrandi D, Konermann C, Beuter-Gunia C, Kresse A, Wurthner J, Kurig S, Beer S, Pfeffer K (2007) Extensive characterization of IFN-induced GTPases mGBP1 to mGBP10 involved in host defense. J Immunol 179:7729–7740

    CAS  PubMed  Google Scholar 

  27. Yang YG, Wang H, Asavaroengchai W, Dey BR (2005) Role of interferon-gamma in GVHD and GVL. Cell Mol Immunol 2:323–329

    CAS  PubMed  Google Scholar 

  28. Bradfute SB, Graubert TA, Goodell MA (2005) Roles of Sca-1 in hematopoietic stem/progenitor cell function. Exp Hematol 33:836–843

    Article  CAS  PubMed  Google Scholar 

  29. Zhang Z-X, Stanford WL, Zhang L (2002) Ly-6A is critical for the function of double negative regulatory T cells. Eur J Immunol 32:1584–1592

    Article  CAS  PubMed  Google Scholar 

  30. Holmes C, Stanford WL (2007) Concise review: stem cell antigen-1: expression, function, and enigma. Stem Cells 25:1339–1347

    Article  CAS  PubMed  Google Scholar 

  31. Lu L, Kim HJ, Werneck MB, Cantor H (2008) Regulation of CD8+ regulatory T cells: interruption of the NKG2A-Qa-1 interaction allows robust suppressive activity and resolution of autoimmune disease. Proc Natl Acad Sci USA 105:19420–19425

    Article  CAS  PubMed  Google Scholar 

  32. Henson ES, Johnston JB, Gibson SB (2008) The role of TRAIL death receptors in the treatment of hematological malignancies. Leuk Lymphoma 49:27–35

    Article  CAS  PubMed  Google Scholar 

  33. Chen JJ, Chou CW, Chang YF, Chen CC (2008) Proteasome inhibitors enhance TRAIL-induced apoptosis through the intronic regulation of DR5: involvement of NF-kappa B and reactive oxygen species-mediated p53 activation. J Immunol 180:8030–8039

    CAS  PubMed  Google Scholar 

  34. Yang YG, Dey BR, Sergio JJ, Pearson DA, Sykes M (1998) Donor-derived interferon gamma is required for inhibition of acute graft-versus-host disease by interleukin 12. J Clin Invest 102:2126–2135

    Article  CAS  PubMed  Google Scholar 

  35. Asavaroengchai W, Wang H, Wang S, Wang L, Bronson R, Sykes M, Yang YG (2007) An essential role for IFN-gamma in regulation of alloreactive CD8 T cells following allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant 13:46–55

    Article  CAS  PubMed  Google Scholar 

  36. Wang H, Asavaroengchai W, Yeap BY, Wang MG, Wang S, Sykes M, Yang YG (2009) Paradoxical effects of IFN-gamma in graft-versus-host disease reflect promotion of lymphohematopoietic graft-versus-host reactions and inhibition of epithelial tissue injury. Blood 113:3612–3619

    Article  CAS  PubMed  Google Scholar 

  37. Capitini CM, Herby S, Milliron M, Anver MR, Mackall CL, Fry TJ (2009) Bone marrow deficient in IFN-{gamma} signaling selectively reverses GVHD-associated immunosuppression and enhances a tumor-specific GVT effect. Blood 113:5002–5009

    CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported in part by grant support from the National Institutes of Health (1R01CA10628) (C.A.M.) and the Brockport High School Leukemia Dance Marathon (C.A.M.).

Author information

Authors and Affiliations

  1. Division of Pediatric Hematology/Oncology, University of Rochester Medical Center, 601 Elmwood Avenue, Box 777, Rochester, NY, 14642, USA

    Jessica C. Shand, Johan Jansson, Yu-Chiao Hsu, Andrew Campbell & Craig A. Mullen

  2. School of Pure and Applied Natural Sciences, University of Kalmar, 391 82, Kalmar, Sweden

    Johan Jansson

Authors
  1. Jessica C. Shand
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Johan Jansson
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yu-Chiao Hsu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Andrew Campbell
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Craig A. Mullen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Craig A. Mullen.

Additional information

J. C. Shand and J. Jansson contributed equally to this work.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Cite this article

Shand, J.C., Jansson, J., Hsu, YC. et al. Differential gene expression in acute lymphoblastic leukemia cells surviving allogeneic transplant. Cancer Immunol Immunother 59, 1633–1644 (2010). https://doi.org/10.1007/s00262-010-0889-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00262-010-0889-y

Keywords

Search

Navigation