title: Anti-leukemic mechanisms of pegylated arginase I in acute lymphoblastic T-cell leukemia.
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.
authors.affiliation: Louisiana State University, Health Sciences Center, New Orleans, LA, USA.
authors.forename: K
authors.initials: K
authors.lastname: Morrow
authors.forename: C P
authors.initials: CP
authors.lastname: Hernandez
authors.forename: P
authors.initials: P
authors.lastname: Raber
authors.forename: L
authors.initials: L
authors.lastname: Del Valle
authors.forename: A M
authors.initials: AM
authors.lastname: Wilk
authors.forename: S
authors.initials: S
authors.lastname: Majumdar
authors.forename: D
authors.initials: D
authors.lastname: Wyczechowska
authors.forename: K
authors.initials: K
authors.lastname: Reiss
authors.forename: P C
authors.initials: PC
authors.lastname: Rodriguez
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001119:Arginase / Q000008:administration & dosage*; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism*; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D010766:Phosphorylation; D011092:Polyethylene Glycols / Q000737:chemistry*; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D054645:Protein Phosphatase 1 / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011994:Recombinant Proteins / Q000627:therapeutic use; D015398:Signal Transduction; D015996:Survival Rate; D019892:eIF-2 Kinase / Q000378:metabolism*
chemical_list: D001119:Arginase; D015852:Eukaryotic Initiation Factor-2; D011092:Polyethylene Glycols; D054645:Protein Phosphatase 1; D017346:Protein Serine-Threonine Kinases; D011994:Recombinant Proteins; D019892:eIF-2 Kinase; C529271:EIF2AK4 protein, human; C087519:PPP1R15A protein, human