title: Targeting apoptosis proteins in hematological malignancies.
abstract: The apoptotic machinery plays a key role in hematopoietic cell homeostasis. Terminally differentiated cells are eliminated, at least in part, by apoptosis, whereas part of the apoptotic machinery, including one or several caspases, is required to go through very specific steps of the differentiation pathways. A number of hematological diseases involve a deregulation of this machinery, which in most cases is a decrease in cell sensitivity to pro-apoptotic signals through over-expression of anti-apoptotic molecules. In some situations however, e.g. in the erythroid lineage of low grade myelodysplastic syndromes, cell sensitivity to apoptosis is increased in a death receptor-dependent manner and cell death pathways are inhibited only when these diseases progress into high grade and acute leukemia. Therapeutic strategies targeting the apoptotic machinery specifically block cell death inhibitors that are over-expressed in transformed cells, mainly Bcl-2-related proteins and Inhibitor of Apoptosis Proteins (IAPs). Another strategy is the activation of the extrinsic pathway to apoptosis, mainly through the death receptor agonist Tumor necrosis factor-Related Apoptosis Inducing Ligand (TRAIL) or agonistic antibodies targeting TRAIL receptors. The use of inhibitors of death receptors could make sense when these receptors are involved in excessive cell death or activation of survival pathways. Most of the drugs targeting apoptotic pathways introduced in clinics have demonstrated their tolerability. Their efficacy, either alone or in combination with other drugs such as demethylating agents and histone deacetylase inhibitors, is currently tested in both myeloid and lymphoid hematological diseases.
authors.affiliation: Inserm UMR 1009, Institut Gustave Roussy, Université Paris-Sud 11, 114 rue Edouard Vaillant, 94805 Villejuif, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Droin
authors.forename: Leslie
authors.initials: L
authors.lastname: Guéry
authors.forename: Naïma
authors.initials: N
authors.lastname: Benikhlef
authors.forename: Eric
authors.initials: E
authors.lastname: Solary
mesh_terms: D020816:Amino Acid Motifs; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D053222:Fas Ligand Protein / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D019337:Hematologic Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D006801:Humans; D008024:Ligands; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D015398:Signal Transduction; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D053222:Fas Ligand Protein; D008024:Ligands; D019253:Proto-Oncogene Proteins c-bcl-2; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human