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Study of Apoptosis-Related Responses of Leukemic Blast Cells to in Vitro Leukemia (2000) 14, 1266–1275 2000 Macmillan Publishers Ltd All rights reserved 0887-6924/00 $15.00 www.nature.com/leu Study of apoptosis-related responses of leukemic blast cells to in vitro anthracycline treatment M-A Belaud-Rotureau1,2, F Durrieu1, G Labroille2, F Lacombe1,3, O Fitoussi4, P Agape4, G Marit2,4, J Reiffers3,4 and F Belloc1,2 1Laboratoire d’He´matologie, Hoˆpital du Haut-Le´veˆque, Pessac; 2Laboratoire Universitaire d’He´matologie, Universite´ Victor Segalen, Bordeaux; 3CNRS-UMR 5540, Universite´ Victor Segalen, Bordeaux; and 4Service des Maladies du Sang, Hoˆpital du Haut-Le´veˆque, Pessac, France Anthracyclines trigger an apoptotic cell death but their molecu- The increase in Fas on tumor cells after low-dose chemo- lar targets are not totally explored. We investigated the apop- therapy may be used as a therapeutic target. Because a syn- totic response of blast cells and lymphocytes from medullary samples of 31 de novo acute leukemia. Mononuclear cells were ergy between Fas-ligand and cytotoxic drugs was observed in treated in vitro by therapeutic concentrations of either dauno- vitro, the Fas increase could enhance tumor cell elimination rubicin (DNR) or idarubicin (IDA) for 1 h, washed and cultured by the immune cells.17 These observations supported the for 18 h. A multivariate analysis using flow cytometry and a rationale for a new therapeutic strategy which could combine CD45 gating on lymphocytes and blast cells was performed. chemotherapy and immunotherapy for cancer treatment.14,18 DNR and IDA induced a Fas enhancement on both leukemic For many years, the anthracyclines have been used in leu- and normal cells. In blast cells the DEVDases were activated kemia treatment and it is known that anthracyclines induce and the caspase 3 was cleaved in relation to phosphatidyl 19–21 serine exposure, showing a caspase-dependent pathway in an apoptotic cell death in a wide range of cultured cells. anthracycline-induced apoptosis. Apoptotic percentages were Therapeutic daunorubicin (DNR) concentrations are about 1– always higher for blast cells than for lymphocytes, confirming 2 µM.22 At these doses, DNR induces apoptosis in U937 and that anthracycline toxicity mainly affected tumor cells. More- HL60 leukemic cell lines.23,24 The Fas apoptotic pathway over, drug-induced apoptosis was not related to spontaneous could at least partially play a role,12–16 involving both death apoptosis, suggesting that variations in response intensities 17,25–27 were due to individual variations of sensitivity rather than to receptor/ligand accumulation on the cell surface and programmed life span time. The apoptotic response of P- activation of the death effectors such as caspases in the cyto- glycoprotein-expressing blast cells was not significant, giving plasm.28 Expression of the mdr-1 gene leads to the multidrug biological argument for the poor prognosis of multidrug resistance phenotype, which is one of the major cause of fail- resistance leukemia. Finally, Fas induction and anthracycline- ure in cancer therapy.29,30 This gene encodes for a 170 kDa induced apoptosis on blast cells were significantly higher when ATP binding glycoprotein (PGP) which acts as a pump to a complete remission was achieved, thus shedding light on 31 potential new prognostic factors in acute leukemia. Leukemia exclude therapeutic agents from the cell, thus decreasing the (2000) 14, 1266–1275. intracellular concentration of the drug and the apoptotic cell Keywords: anthracycline; apoptosis; leukemia; Fas; caspase response.32 However, the mechanisms mediating the anthra- cycline-induced killing of leukemic blast cells are not defini- tively known and a possible correlation between the apoptotic Introduction potential of blast cells and the clinical outcome of patients has never been explored. Fas (APO-1, CD95) is a tumor necrosis factor family membrane In the present work, we investigated the apoptotic response protein which triggers programmed cell death when engaged of in vitro anthracycline-treated leukemic blast cells and nor- by anti-Fas antibody or Fas-ligand.1 The death pathway mal lymphocytes isolated from medullary samples of 31 initiated by Fas activation involves a series of death-induced patients suffering from de novo acute leukemia (AL). Some molecules.1 Fas-associating protein with death domain (FADD) mechanisms of cellular drug resistance (PGP expression, or MORT-1 is recruited to Fas upon its engagement.2,3 FADD apoptotic deficiency) and others of cell death (Fas expression, then binds FADD-like ICE (FLICE) or MORT-1-associated CED- DEVDase activation, caspase 3 activation, phosphatidyl serine 3 homologue.4,5 The association with the Fas death-inducing exposure) were assayed. A possible correlation between these signaling complex activates FLICE,6 followed by activation of parameters and the clinical outcome of patients was then the caspase proteolytic cascade and apoptosis.7 Fas is found on examined. We clearly show that both anthracyclines (DNR immunity cells (lymphocytes, NK cells, monocytes) but also on and idarubicin (IDA)) induce apoptosis in leukemic blast cells numerous tumor cells such as tumor cell lines or leukemic blast and lymphocytes. This death was accompanied by a Fas cells.8,9 Its expression is decreased during tumor cell enhance- expression enhancement on both lymphocytes and blast cells. ment or during the cell acquisition of the drug resistance Caspase 3 was cleaved and consequently activated and the phenotype.10,11 caspase 3 cleavage was correlated with phosphatidyl serine Several cytotoxic drugs (cisplatin, doxorubicin, bleomycin, exposure. When PGP was expressed on the cell membrane, mitomycin, methotrexate) as well as ionizing radiation can the apoptotic potential of blast cells was strongly decreased, sensitize many tumor cells to Fas-induced apoptosis.12–16 This giving biological argument for the poor prognosis of PGP- sensitization is mediated by a transcriptional and a post- positive acute leukemia. The apoptotic response intensity of transcriptional regulation of the fas gene, which leads to blast cells was significantly associated with the clinical out- receptor accumulation on the drug-treated membrane cells. come of patients, thus shedding light on potential new prognostic factors in acute leukemia. Correspondence: F Belloc, De´partement de Cytome´trie en Flux, Patients and methods Laboratoire d’He´matologie, Hoˆpital Haut-Le´veˆque, 33604 Pessac Cedex, France; Fax: 33 556 55 68 09 The study included 30 patients with previously untreated de Received 25 November 1999; accepted 24 February 2000 novo AL who were treated in our institution between Nov- Anthracycline-induced apoptosis in leukemia M-A Belaud-Rotureau et al 1267 ember 1998 and August 1999. Another patient who relapsed (Gibco-BRL), 100 units/ml penicillin (Gibco-BRL), 50 µg/ml 1 year after the end of chemotherapy was included. One streptomycin (Gibco-BRL). Finally, the cell concentration was patient was not followed up for his clinical evolution because adjusted to 1 × 106 cells/ml. he was treated in another institution. All the patients gave informed consent. Their disease was classified according to the recommendations of the French– Cell incubation with daunorubicin or idarubicin American–British (FAB) committee.33 Twenty-four acute myeloid leukemia (AML) and seven acute non-myeloid leuke- The cell suspension was distributed in three tubes. One was mia (ANML) were found. According to the type of AL, the incubated without anthracyclines (NT) for 1 h at 37°C, the induction chemotherapy varied but all patients received an second was incubated with 1 µM daunorubicin (DNR, RPR- anthracycline, either DNR or IDA. On September 1999, 15 Bellon, Neuilly, France) for 1 h at 37°C and the third was patients had survived in complete remission (SCR) and 10 incubated with 0.2 µM idarubicin (IDA, Pharmacia, Saint patients died after treatment failure (DTF). The remaining were Quentin en Yvelines, France) for 1 h at 37°C. Then, BM-MNC not classified because no post-mortem biopsies were done or were washed, resuspended in CM and cultured for 18 h in ° because there was not enough distance from the first chemo- humidified 95% O2 and 5% CO2 atmosphere at 37 C. therapy induction. Complete remission was defined as the presence of fewer than 5% blast cells in a cellular BM smear, and the absence of circulating blast cells and extramedullary Cellular response to anthracycline exposure leukemic cell infiltration. The clinical and hematological characteristics are summarized in Table 1. Flow cytometry (FCM) analysis: Fas and PGP expression, apoptosis percentage, and caspase 3 activation were assayed by FCM with an EPICS XL cytometer (Coulter, Margency, BM collection and preparation France). The CD45 differential expression allowed a selective gating of lymphocytes and blast cells34 and the cell response Before induction chemotherapy, BM aspirates were collected to anthracycline exposure was thus assessed simultaneously for diagnosis and 1 ml was sampled on sodium heparinate in these two cellular populations. tubes (Roche, France). Bone marrow mononuclear cells (BM- After centrifugation (5 min, 400 g), 5 × 105 cells from NT, MNC) were isolated by centrifuging half diluted BM over Lym- DNR and IDA suspensions were resuspended in 100 µl phos- phoprep (Nyegeaard, Oslo, Norway) for 40 min at 400 g. BM- phate buffer saline (PBS, Eurobio, France) supplemented with MNC were washed in RPMI 1640 (Gibco-BRL, Eragny, 10% FCS (PBS-FCS) and labeled with 5 µl of PC5-conjugated France) and
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