IN-VITRO DOWN-REGULATION OF BCL-2 EXPRESSION BY ALL-TRANS-RETINOIC ACID IN AML BLASTS

Using flow cytometry, we have investigated the effects of 0.5 mu M all -trans-retinoic acid (ATRA) on bcl-2 expression in the blast cells of 25 acute myeloblastic leukemia (AML) patients and the HL-60 cell line after incubation for 6 days. We observed a significant decrease of bcl -2 expression after treatment with ATRA in 12 of 25 AML samples and th e HL-60 cells. The mean fluorescence intensity (MFI) ratio for the bcl -2 levels of the ATRA responders (n = 12) was reduced to 7.9+/-4.8 fol lowing incubation with ATRA compared with 10.9+/-6.5 (mean+/-SD) for c ontrol samples incubated without ATRA (p=0.011). There was no signific ant difference between the baseline bcl-2 MFI ratio in the ATRA respon ders (11.14+/-7, n=12) and the non responders (14.18+/-11.3, n=13, p=0 .432). The down-regulation of bcl-2 expression by ATRA was not signifi cantly associated with CD34-negative or -positive AML. There was no co rrelation between AML subtypes and regulation of bcl-2 expression by A TRA. Complete remission and overall survival were not significantly im proved in bcl-2 down-regulated cases. Our data confirm that ATRA can d own-regulate the bcl-2 expression in AML blasts. Because many che moth erapeutic agents also operate through the activation of programmed cel l death and bcl-2 levels are positively associated with resistance to apoptosis, ATRA can be used in combination chemotherapy to increase th e chemosensitivity of some patients with AML.