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

Anti-leukemic mechanisms of pegylated arginase I in acute lymphoblastic T-cell leukemia

Leukemia volume 27, pages 569–577 (2013)Cite this article

Subjects

Abstract

New treatments for adults with acute lymphoblastic T-cell leukemia (T-ALL) are urgently needed, as the current rate of overall remission in these patients is only about 40 percent. We recently showed the potential therapeutic benefit of the pegylated-human-arginase I (peg-Arg I) in T-ALL. However, the mechanisms by which peg-Arg I induces an anti-T-ALL effect remained unknown. Our results show the induction of T-ALL cell apoptosis by peg-Arg I, which associated with a global arrest in protein synthesis and with the phosphorylation of the eukaryotic-translation-initiation factor 2 alpha (eIF2α). Inhibition of eIF2α phosphorylation in T-ALL cells prevented the apoptosis induced by peg-Arg I, whereas the expression of a phosphomimetic eIF2α form increased the sensibility of T-ALL cells to peg-Arg I. Phosphorylation of eIF2α by peg-Arg I was mediated through kinases PERK and GCN2 and down-regulation of phosphatase GADD34. GCN2 and decreased GADD34 promoted T-ALL cell apoptosis after treatment with peg-Arg I, whereas PERK had an unexpected anti-apoptotic role. Additional results showed that phospho-eIF2α signaling further increased the anti-leukemic effects induced by peg-Arg I in T-ALL-bearing mice. These results suggest the central role of phospho-eIF2α in the anti-T-ALL effects induced by peg-Arg I and support its study as a therapeutic target.

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

References

  1. Inaba H, Bhojwani D, Pauley JL, Pei D, Cheng C, Metzger ML et al. Combination chemotherapy with clofarabine, cyclophosphamide, and etoposide in children with refractory or relapsed haematological malignancies. Br J Haematol 2012; 156: 275–279.

    Article  CAS  Google Scholar 

  2. Pui CH, Sandlund JT, Pei D, Campana D, Rivera GK, Ribeiro RC et al. Improved outcome for children with acute lymphoblastic leukemia: results of Total Therapy Study XIIIB at St Jude Children’s Research Hospital. Blood 2004; 104: 2690–2696.

    Article  CAS  Google Scholar 

  3. Tanosaki R, Tobinai K . Adult T-cell leukemia-lymphoma: current treatment strategies and novel immunological approaches. Expert Rev Hematol 2010; 3: 743–753.

    Article  CAS  Google Scholar 

  4. Laport GF, Larson RA . Treatment of adult acute lymphoblastic leukemia. Semin Oncol 1997; 24: 70–82.

    CAS  PubMed  Google Scholar 

  5. Hernandez CP, Morrow K, Lopez-Barcons LA, Zabaleta J, Sierra R, Velasco C et al. Pegylated arginase I: a potential therapeutic approach in T-ALL. Blood 2010; 115: 5214–5221.

    Article  CAS  Google Scholar 

  6. Holcik M, Sonenberg N . Translational control in stress and apoptosis. Nat Rev Mol Cell Biol 2005; 6: 318–327.

    Article  CAS  Google Scholar 

  7. Woo CW, Cui D, Arellano J, Dorweiler B, Harding H, Fitzgerald KA et al. Adaptive suppression of the ATF4-CHOP branch of the unfolded protein response by toll-like receptor signalling. Nat Cell Biol 2009; 11: 1473–1480.

    Article  CAS  Google Scholar 

  8. Blander JM, Amsen D . Immunology. amino acid addiction. Science 2009; 324: 1282–1283.

    Article  CAS  Google Scholar 

  9. Jousse C, Oyadomari S, Novoa I, Lu P, Zhang Y, Harding HP et al. Inhibition of a constitutive translation initiation factor 2alpha phosphatase, CReP, promotes survival of stressed cells. J Cell Biol 2003; 163: 767–775.

    Article  CAS  Google Scholar 

  10. Novoa I, Zeng H, Harding HP, Ron D . Feedback inhibition of the unfolded protein response by GADD34-mediated dephosphorylation of eIF2alpha. J Cell Biol 2001; 153: 1011–1022.

    Article  CAS  Google Scholar 

  11. Chan SM, Weng AP, Tibshirani R, Aster JC, Utz PJ . Notch signals positively regulate activity of the mTOR pathway in T-cell acute lymphoblastic leukemia. Blood 2007; 110: 278–286.

    Article  CAS  Google Scholar 

  12. Weng AP, Ferrando AA, Lee W, Morris JP, Silverman LB, Sanchez-Irizarry C et al. Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia. Science 2004; 306: 269–271.

    Article  CAS  Google Scholar 

  13. Sood R, Porter AC, Olsen DA, Cavener DR, Wek RC . A mammalian homologue of GCN2 protein kinase important for translational control by phosphorylation of eukaryotic initiation factor-2alpha. Genetics 2000; 154: 787–801.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Cheng PN, Lam TL, Lam WM, Tsui SM, Cheng AW, Lo WH et al. Pegylated recombinant human arginase (rhArg-peg5,000mw) inhibits the in vitro and in vivo proliferation of human hepatocellular carcinoma through arginine depletion. Cancer Res 2007; 67: 309–317.

    Article  CAS  Google Scholar 

  15. Muaddi H, Majumder M, Peidis P, Papadakis AI, Holcik M, Scheuner D et al. Phosphorylation of eIF2alpha at serine 51 is an important determinant of cell survival and adaptation to glucose deficiency. Mol Biol Cell 2010; 21: 3220–3231.

    Article  CAS  Google Scholar 

  16. Rodriguez PC, Quiceno DG, Ochoa AC . L-arginine availability regulates T-lymphocyte cell-cycle progression. Blood 2007; 109: 1568–1573.

    Article  CAS  Google Scholar 

  17. Rodriguez PC, Ernstoff MS, Hernandez C, Atkins M, Zabaleta J, Sierra R et al. Arginase I-producing myeloid-derived suppressor cells in renal cell carcinoma are a subpopulation of activated granulocytes. Cancer Res 2009; 69: 1553–1560.

    Article  CAS  Google Scholar 

  18. Jousse C, Averous J, Bruhat A, Carraro V, Mordier S, Fafournoux P . Amino acids as regulators of gene expression: molecular mechanisms. Biochem Biophys Res Commun 2004; 313: 447–452.

    Article  CAS  Google Scholar 

  19. Boyce M, Bryant KF, Jousse C, Long K, Harding HP, Scheuner D et al. A selective inhibitor of eIF2alpha dephosphorylation protects cells from ER stress. Science 2005; 307: 935–939.

    Article  CAS  Google Scholar 

  20. Izzo F, Marra P, Beneduce G, Castello G, Vallone P, De R V et al. Pegylated arginine deiminase treatment of patients with unresectable hepatocellular carcinoma: results from phase I/II studies. J Clin Oncol 2004; 22: 1815–1822.

    Article  CAS  Google Scholar 

  21. Ascierto PA, Scala S, Castello G, Daponte A, Simeone E, Ottaiano A et al. Pegylated arginine deiminase treatment of patients with metastatic melanoma: results from phase I and II studies. J Clin Oncol 2005; 23: 7660–7668.

    Article  CAS  Google Scholar 

  22. Highfill SL, Rodriguez PC, Zhou Q, Goetz CA, Koehn BH, Veenstra R et al. Bone marrow myeloid-derived suppressor cells (MDSCs) inhibit graft-versus-host disease (GVHD) via an arginase-1-dependent mechanism that is up-regulated by interleukin-13. Blood 2010; 116: 5738–5747.

    Article  CAS  Google Scholar 

  23. Hellen CU, Sarnow P . Internal ribosome entry sites in eukaryotic mRNA molecules. Genes Dev 2001; 15: 1593–1612.

    Article  CAS  Google Scholar 

  24. Schneider R, Agol VI, Andino R, Bayard F, Cavener DR, Chappell SA et al. New ways of initiating translation in eukaryotes. Mol Cell Biol 2001; 21: 8238–8246.

    Article  CAS  Google Scholar 

  25. Talvas J, Obled A, Fafournoux P, Mordier S . Regulation of protein synthesis by leucine starvation involves distinct mechanisms in mouse C2C12 myoblasts and myotubes. J Nutr 2006; 136: 1466–1471.

    Article  CAS  Google Scholar 

  26. Schewe DM, guirre-Ghiso JA . Inhibition of eIF2alpha dephosphorylation maximizes bortezomib efficiency and eliminates quiescent multiple myeloma cells surviving proteasome inhibitor therapy. Cancer Res 2009; 69: 1545–1552.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank Daniel Nguyen, BS for his technical assistance in some of the experiments. This work was supported in part by NIH-NCRR (COBRE) grants P20RR021970 and 1R21CA162133 to PCR.

Author information

Authors and Affiliations

  1. Stanley S Scott Cancer Center, Louisiana State University, Health Sciences Center, New Orleans, LA, USA

    K Morrow, C P Hernandez, P Raber, L Del Valle, A M Wilk, S Majumdar, D Wyczechowska, K Reiss & P C Rodriguez

  2. Department of Microbiology Immunology and Parasitology, Louisiana State University, Health Sciences Center, New Orleans, LA, USA

    P Raber, L Del Valle & P C Rodriguez

Authors
  1. K Morrow
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. C P Hernandez
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. P Raber
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. L Del Valle
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. A M Wilk
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. S Majumdar
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. D Wyczechowska
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. K Reiss
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. P C Rodriguez
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to P C Rodriguez.

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

Morrow, K., Hernandez, C., Raber, P. et al. Anti-leukemic mechanisms of pegylated arginase I in acute lymphoblastic T-cell leukemia. Leukemia 27, 569–577 (2013). https://doi.org/10.1038/leu.2012.247

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/leu.2012.247

Keywords

This article is cited by

Search

Advanced search

Quick links