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:

Sensitivity and Resistance to Therapy

Resistance of infant leukemia with MLL rearrangement to tumor necrosis factor-related apoptosis-inducing ligand: a possible mechanism for poor sensitivity to antitumor immunity

Leukemia volume 20, pages 2119–2129 (2006)Cite this article

Abstract

Malignant cells generally acquire some immune escape mechanisms for clonal expansion. Immune escape mechanisms also contribute to the failure of graft-versus-leukemia (GVL) effect after allogeneic hematopoietic stem cell transplantation (allo-SCT). Infant leukemias with mixed-lineage leukemia (MLL) rearrangement have a remarkably short latency, and GVL effect after allo-SCT has not been clearly evidenced in these leukemias. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)- and FasL-mediated cytotoxic pathways play important roles in cytotoxic T-lymphocyte- and natural killer cell-mediated antitumor immunity and optimal GVL activity. We investigated the in vitro sensitivity of MLL-rearranged acute lymphoblastic leukemia (ALL) and acute myeloblastic leukemia (AML) cells to TRAIL- and FasL-mediated cytotoxicity. Most of cell lines and primary leukemia cells were highly resistant to TRAIL primarily owing to low cell-surface expression of death receptors in ALL and simultaneous expression of decoy receptors in AML. Nearly half of cell lines and majority of primary leukemia cells showed low sensitivity to FasL. These results suggest that resistance to death-inducing ligands, particularly to TRAIL, could be one of the mechanisms for a rapid clonal expansion and a poor sensitivity to the GVL effect in infant leukemias with MLL rearrangement.

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

Similar content being viewed by others

Accession codes

Accessions

GenBank/EMBL/DDBJ

References

  1. Biondi A, Cimino G, Pieters R, Pui CH . Biological and therapeutic aspects of infant leukemia. Blood 2000; 96: 24–33.

    CAS  PubMed  Google Scholar 

  2. Ayton PM, Cleary ML . Molecular mechanisms of leukemogenesis mediated by MLL fusion proteins. Oncogene 2001; 20: 5695–5707.

    Article  CAS  PubMed  Google Scholar 

  3. Daser A, Rabbitts TH . Extending the repertoire of the mixed-lineage leukemia gene MLL in leukemogenesis. Genes Dev 2004; 18: 965–974.

    Article  CAS  PubMed  Google Scholar 

  4. Greaves MF, Maia AT, Wiemels JT, Ford AM . Leukemia in twins: lessons in natural history. Blood 2003; 102: 2321–2333.

    Article  CAS  PubMed  Google Scholar 

  5. Dunn GP, Old LJ, Schreiber RD . The immunobiology of cancer immunosurveillance and immunoediting. Immunity 2004; 21: 137–148.

    Article  CAS  PubMed  Google Scholar 

  6. Khong HT, Restifo NP . Natural selection of tumor variants in the generation of ‘tumor escape’ phenotypes. Nat Immunol 2002; 3: 999–1005.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Kolb HJ, Schmid C, Barrett AJ, Schendel DJ . Graft-versus-leukemia reactions in allogeneic chimeras. Blood 2003; 103: 767–776.

    Article  PubMed  Google Scholar 

  8. Pui CH, Gaynon PS, Boyett JM, Chessells JM, Baruchel A, Kamps W et al. Outcome of treatment in childhood acute lymphoblastic leukaemia with rearrangements of the 11q23 chromosomal region. Lancet 2002; 359: 1909–1915.

    Article  PubMed  Google Scholar 

  9. Kosaka Y, Koh K, Kinukawa N, Wakazono Y, Isoyama K, Oda T et al. Infant acute lymphoblastic leukemia with MLL gene rearrangements: outcome following intensive chemotherapy and hematopoietic stem cell transplantation. Blood 2004; 104: 3527–3534.

    Article  CAS  PubMed  Google Scholar 

  10. Smyth MJ, Takeda K, Hayakawa Y, Peschon JJ, van den Brink MR, Yagita H . Nature's TRAIL – on a path to cancer immunotherapy. Immunity 2003; 18: 1–6.

    Article  CAS  PubMed  Google Scholar 

  11. Kagi D, Vignaux F, Ledermann B, Burki K, Depraetere V, Nagata S et al. Fas and perforin pathways as major mechanisms of T cell-mediated cytotoxicity. Science 1994; 265: 528–530.

    Article  CAS  PubMed  Google Scholar 

  12. Lowin B, Hahne M, Mattmann C, Tschopp J . Cytolytic T-cell cytotoxicity is mediated through perforin and Fas lytic pathways. Nature 1994; 370: 650–652.

    Article  CAS  PubMed  Google Scholar 

  13. Smyth MJ, Cretney E, Takeda K, Wiltrout RH, Sedger LM, Kayagaki N et al. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) contributes to interferon gamma-dependent natural killer cell protection from tumor metastasis. J Exp Med 2001; 193: 661–670.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Takeda K, Hayakawa Y, Smyth MJ, Kayagaki N, Yamaguchi N, Kakuta S et al. Involvement of tumor necrosis factor-related apoptosis-inducing ligand in surveillance of tumor metastasis by liver natural killer cells. Nat Med 2001; 7: 94–100.

    Article  CAS  PubMed  Google Scholar 

  15. Cretney E, Takeda K, Yagita H, Glaccum M, Peschon JJ, Smyth MJ . Increased susceptibility to tumor initiation and metastasis in TNF-related apoptosis-inducing ligand-deficient mice. J Immunol 2002; 168: 1356–1361.

    Article  CAS  PubMed  Google Scholar 

  16. Takeda K, Smyth MJ, Cretney E, Hayakawa Y, Kayagaki N, Yagita H et al. Critical role for tumor necrosis factor-related apoptosis-inducing ligand in immune surveillance against tumor development. J Exp Med 2002; 195: 161–169.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Schmaltz C, Alpdogan O, Kappel BJ, Muriglan SJ, Rotolo JA, Ongchin J et al. T cells require TRAIL for optimal graft-versus-tumor activity. Nat Med 2002; 8: 1433–1437.

    Article  CAS  PubMed  Google Scholar 

  18. Pan G, O'Rourke K, Chinnaiyan AM, Gentz R, Ebner R, Ni J et al. The receptor for the cytotoxic ligand TRAIL. Science 1997; 276: 111–113.

    Article  CAS  PubMed  Google Scholar 

  19. Pan G, Ni J, Wei YF, Yu G, Gentz R, Dixit VM . An antagonist decoy receptor and death domain-containing receptor for TRAIL. Science 1997; 277: 815–821.

    Article  CAS  PubMed  Google Scholar 

  20. Sheridan JP, Marsters SA, Pitti RM, Gurney A, Skubatch M, Baldwin D et al. Control of TRAIL-induced apoptosis by a family of signaling and decoy receptors. Science 1997; 277: 818–821.

    Article  CAS  PubMed  Google Scholar 

  21. Degli-Esposti MA, Dougall WC, Smolak PJ, Waugh JY, Smith CA, Goodwin RG . The novel receptor TRAIL-R4 induces NF-kappaB and protects against TRAIL-mediated apoptosis, yet retains an incomplete death domain. Immunity 1997; 7: 813–820.

    Article  CAS  PubMed  Google Scholar 

  22. Taketani T, Taki T, Sugita K, Furuichi Y, Ishii E, Hanada R et al. FLT3 mutations in the activation loop of tyrosine kinase domain are frequently found in infant ALL with MLL rearrangements and pediatric ALL with hyperdiploidy. Blood 2004; 103: 1085–1088.

    Article  CAS  PubMed  Google Scholar 

  23. Uno K, Inukai T, Kayagaki N, Goi K, Sato H, Nemoto A et al. TNF-related apoptosis-inducing ligand (TRAIL) frequently induces apoptosis in Philadelphia chromosome-positive leukemia cells. Blood 2003; 101: 3658–3667.

    Article  CAS  PubMed  Google Scholar 

  24. Scaife CL, Kuang J, Wills JC, Trowbridge DB, Gray P, Manning BM et al. Nuclear factor kappaB inhibitors induce adhesion-dependent colon cancer apoptosis: implications for metastasis. Cancer Res 2002; 62: 6870–6878.

    CAS  PubMed  Google Scholar 

  25. Inukai T, Inoue A, Kurosawa H, Goi K, Shinjyo T, Ozawa K et al. SLUG, a ces-1-related zinc finger transcription factor gene with antiapoptotic activity, is a downstream target of the E2A-HLF oncoprotein. Mol Cell 1999; 4: 343–352.

    Article  CAS  PubMed  Google Scholar 

  26. Chaudhary PM, Eby M, Jasmin A, Bookwalter A, Murray J, Hood L . Death receptor 5, a new member of the TNFR family, and DR4 induce FADD-dependent apoptosis and activate the NF-kappaB pathway. Immunity 1997; 7: 821–830.

    Article  CAS  PubMed  Google Scholar 

  27. Berenbaum MC . What is synergy? Pharmacol Rev 1989; 41: 93–141.

    CAS  PubMed  Google Scholar 

  28. Arico M, Valsecchi MG, Camitta B, Schrappe M, Chessells J, Baruchel A et al. Outcome of treatment in children with Philadelphia chromosome-positive acute lymphoblastic leukemia. N Engl J Med 2000; 342: 998–1006.

    Article  CAS  PubMed  Google Scholar 

  29. Riccioni R, Pasquini L, Mariani G, Saulle E, Rossini A, Diverio D et al. TRAIL decoy receptors mediate resistance of acute myeloid leukemia cells to TRAIL. Haematologica 2005; 90: 612–624.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported in part by research grants from the Ministry of Education, Science, and Culture, Japan. XZ was supported in part by Japan China Sasagawa Medical Fellowship.

Author information

Author notes

  1. T Inukai and X Zhang: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Pediatrics, School of Medicine, University of Yamanashi, Yamanashi, Japan

    T Inukai, X Zhang, M Goto, K Hirose, K Uno, K Akahane, A Nemoto, K Goi, H Sato, K Takahashi, H Honna, K Kagami, S Nakazawa & K Sugita

  2. Bioinformatics Support Section, Center for Life Science Research, University of Yamanashi, Yamanashi, Japan

    K Nakamoto

  3. Department of Immunology, Juntendo University School of Medicine, Tokyo, Japan

    H Yagita & K Okumura

  4. Laboratory of Immunology, Saitama Shakaihoken Hospital, Saitama, Japan

    T Koyama-Okazaki

Authors
  1. T Inukai
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. X Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M Goto
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. K Hirose
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. K Uno
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. K Akahane
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. A Nemoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. K Goi
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. H Sato
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. K Takahashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. H Honna
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. K Kagami
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. K Nakamoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. H Yagita
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. K Okumura
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. T Koyama-Okazaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. S Nakazawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. K Sugita
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to T Inukai.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Inukai, T., Zhang, X., Goto, M. et al. Resistance of infant leukemia with MLL rearrangement to tumor necrosis factor-related apoptosis-inducing ligand: a possible mechanism for poor sensitivity to antitumor immunity. Leukemia 20, 2119–2129 (2006). https://doi.org/10.1038/sj.leu.2404429

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.leu.2404429

Keywords

This article is cited by

Search

Advanced search

Quick links