Changes in apoptosis-related pathways in acute myelocytic leukemia.
Expression analysis of apoptotic genes was performed for 15 patients with acute myelocytic leukemia (AML) at the time of diagnosis to identify genes and signaling pathways involved in the regulation of cell survival and apoptosis during leukemogenesis. cDNA array analysis revealed 34 genes whose expression was significantly different compared to others. Tumor suppressor genes TP53 and CDKN2A were downregulated and protooncogenes JUN and GRB10 were upregulated. Furthermore, several cellular signaling pathways acting either in cell cycle regulation or in apoptosis were altered. Deregulation was found in pathways that contribute to genomic stability (by downregulation of either TP53 or CSE1L and by upregulation of GADD45A) and regulate cell cycle progression (by downregulation of CDKN2A and upregulation of RBBP4, CDC37, and NEDD5). Alterations at the transcriptional level were identified, namely, upregulation of JUN and E2F5. Abnormalities were observed in the regulation of the caspases through upregulation of CASP8 and by altered expression of BCL2-related pathway. Extrinsic apoptotic signals mediated by IGFs were deregulated and the glutathione detoxification pathway was downregulated. These findings provide insight into the regulation of balance between apoptosis and cell proliferation signals, and suggest that these genes and pathways may have an important role in the pathogenesis of AML.
Casas
Sílvia
S
Departments of Pathology and Medical Genetics, Haartman Institute and Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland.
Ollila
Juha
J
Aventín
Anna
A
Vihinen
Mauno
M
Sierra
Jorge
J
Knuutila
Sakari
S
D000328:Adult; D017209:Apoptosis / Q000235:genetics*; D020169:Caspases / Q000378:metabolism; D019070:Cell Lineage; D005260:Female; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D007223:Infant; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D014409:Tumor Necrosis Factor-alpha; D016159:Tumor Suppressor Protein p53; D017526:Receptor, IGF Type 1; D020169:Caspases; D005978:Glutathione