Application of flow cytometry to molecular medicine: detection of tumor necrosis factor-related apoptosis-inducing ligand receptors in acute myeloid leukaemia blasts.
TRAIL (tumor necrosis factor-related apoptosis-inducing ligand), a cytokine belonging to the TNF (tumor necrosis factor) family, is currently regarded as a potential anti-cancer agent. Nevertheless, several types of cancer cells display a low sensitivity to TRAIL or are completely resistant to this pro-apoptotic cytokine. TRAIL signalling is dependent on four receptors. Two of them, death receptors 4 and 5 (DR4 and DR5), induce apoptosis, whereas decoy receptors 1 and 2 (DcR1 and DcR2) are unable to evoke cell death upon TRAIL binding. TRAIL resistance may be related to the expression of TRAIL decoy receptors. TRAIL has been proposed as a novel therapeutic agent for the treatment of haematological disorders, including acute myeloid leukaemia (AML). Surprisingly, however, very limited information is available concerning the expression of TRAIL receptors in AML blasts. Here, we have evaluated, using flow cytometry, TRAIL receptor surface expression and sensitivity to TRAIL-dependent apoptosis of AML blasts from 30 patients. We observed frequent expression of TRAIL DcR1 and DcR2, while expression of DR4 and DR5 was less frequent. Nevertheless, the expression of DR4 or DR5 in leukaemic cells was always matched by a similar expression of one of the decoy receptors. Leukaemic blasts were invariably resistant, even to a high concentration (1000 ng/ml) of TRAIL. We suggest that AML blasts are resistant to TRAIL apoptosis in vitro. Therefore, it is unlikely that TRAIL alone might be used in the future as an innovative pharmacological agent for the treatment of AML.
Cappellini
Alessandra
A
Dipartimento di Scienze Motorie e della Salute, Sezione di Anatomia, Università di Cassino, 03043 Cassino, Italy.
Mantovani
Irina
I
Tazzari
Pier Luigi
PL
Grafone
Tiziana
T
Martinelli
Giovanni
G
Cocco
Lucio
L
Martelli
Alberto M
AM
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism* / Q000494:pharmacology; D045744:Cell Line, Tumor; D002463:Cell Membrane Permeability; D005260:Female; D005434:Flow Cytometry / Q000379:methods*; D006098:Granulocytes / Q000378:metabolism; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism* / Q000494:pharmacology; D008875:Middle Aged; D009000:Monocytes / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000032:analysis* / Q000378:metabolism; D012680:Sensitivity and Specificity; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism* / Q000494:pharmacology
D051017:Apoptosis Regulatory Proteins; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; D018124:Receptors, Tumor Necrosis Factor; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha