title: Granulocytic maturation in cultures of acute myeloid leukemia is not always accompanied by increased apoptosis.
abstract: In this issue of the Journal, Soucek et al. challenge the assumption that increased functional granulocytic maturation of HL-60, an ATRA-responsive acute myeloid leukemia cell line devoid of the APL-specific PML-RARalpha fusion protein, results in more rapid or more sustained cell death. In this model cell line, the authors demonstrate that TGFbeta1, a well-known haemopoietic growth factor, enhances retinoid-dependent cyto-differentiation and growth arrest while inhibiting apoptosis. Concomitantly, treatment of HL-60 cells with the combination of TGFbeta1 and the retinoid partially suppresses ATRA-dependent induction of TRAIL. This is a death receptor ligand of the TNF family implicated in the paracrine mechanism underlying the apoptotic action of ATRA in APL blasts The protein activates the death-receptor-dependent or extrinsic apoptotic pathway, which is associated with caspase-8 activation. Down-regulation of TRAIL is correlated to an increase in the levels of the anti-apoptotic c-FLIP(L) and Mcl-1 proteins that are likely to be involved in the suppression of caspase-8 activation and apoptosis.
authors.forename: Enrico
authors.initials: E
authors.lastname: Garattini
authors.forename: Mineko
authors.initials: M
authors.lastname: Terao
mesh_terms: D000208:Acute Disease; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism / Q000494:pharmacology; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D053181:Caspase 8; D020169:Caspases / Q000187:drug effects / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D006098:Granulocytes / Q000166:cytology; D018922:HL-60 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000187:drug effects / Q000378:metabolism; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism* / Q000473:pathology; D008562:Membrane Glycoproteins / Q000378:metabolism / Q000494:pharmacology; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins / Q000187:drug effects / Q000378:metabolism; D010446:Peptide Fragments / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000187:drug effects / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D053773:Transforming Growth Factor beta1; D014212:Tretinoin / Q000037:antagonists & inhibitors / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000494:pharmacology
chemical_list: D051017:Apoptosis Regulatory Proteins; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins; D010446:Peptide Fragments; D019253:Proto-Oncogene Proteins c-bcl-2; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha; C464671:transforming growth factor beta1 (41-65); D014212:Tretinoin; C505530:CASP8 protein, human; D053181:Caspase 8; D020169:Caspases