A probable role for trail-induced apoptosis in the pathogenesis of marrow failure. Implications from an in vitro model and from marrow of aplastic anemia patients.
Aplastic anemia (AA) is a syndrome of hematopoietic failure involving increased apoptosis of stem cells. In order to investigate the molecular mechanisms participated in the process of marrow failure, we created an in vitro model of hematopoietic cell suppression, by continuous addition of TNF-alpha and IFN-gamma in an vitro long-term bone marrow culture system. An up-regulation of Fas expression was observed in CD34+ cells in cytokine treated cultures, compared to controls. This was accompanied by significant TRAIL and decreased caspase 3 mRNA expression, whereas the expression of Bcl-2 family members was low (Bcl-xl) or absent (Bcl-2, Bax). The expression of these apoptotic genes was also investigated in aplastic anemia patients. Apart from Fas mRNA expression in total marrow and/or CD34+ cells, TRAIL mRNA expression was found only in CD34+ cells in active disease while in total marrow cell compartment this remains a constant finding even in patients in remission. The above data are in agreement with previous studies proposing a major role for the extrinsic apoptosis pathway in the pathogenesis of aplastic anemia and additionally introduce TRAIL as a probable important molecule in the process.
Kakagianni
Theodora
T
Hematology Division, Department of Internal Medicine, University Hospital of Patras, Rion, Patras 26500, Greece. dsiasou@med.upatras.gr
Giannakoulas
Nikolaos C
NC
Thanopoulou
Eleni
E
Galani
Anastasia
A
Michalopoulou
Sotiria
S
Kouraklis-Symeonidis
Alexandra
A
Zoumbos
Nicholas C
NC
D000328:Adult; D000368:Aged; D000741:Anemia, Aplastic / Q000378:metabolism* / Q000473:pathology; D018952:Antigens, CD34 / Q000096:biosynthesis; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis*; D002478:Cells, Cultured; D005260:Female; D006412:Hematopoietic Stem Cells / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D008297:Male; D008562:Membrane Glycoproteins / Q000096:biosynthesis*; D008875:Middle Aged; D015398:Signal Transduction / Q000187:drug effects; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects; D051028:bcl-2-Associated X Protein / Q000096:biosynthesis; D051020:bcl-X Protein / Q000096:biosynthesis; D019014:fas Receptor / Q000096:biosynthesis
D018952:Antigens, CD34; D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C494811:BCL2L1 protein, human; D008562:Membrane Glycoproteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; D019014:fas Receptor; D007371:Interferon-gamma