title: Bcr-abl translocation can occur during the induction of multidrug resistance and confers apoptosis resistance on myeloid leukemic cell lines.
abstract: Apoptosis was studied in parental and mdr-1 expressing U937, HL60 and K562 myeloid leukemic cell lines using mdr unrelated inducers of apoptosis such as Ara-C, cycloheximide, serum deprivation, ceramide, monensin and UV irradiation. Apoptosis was efficiently induced by all these treatments in U937 and HL60 cells while K562 cells exhibited an apoptosis-resistant phenotype except with UV and monensin. The pattern of apoptosis resistance in mdr-1 expressing U937 (U937-DR) and HL60 (HL60-DR100) was similar to that presented by K562. This apoptosis-resistant phenotype of mdr cells was not overcome by concentrations of verapamil inhibiting the P-gp 170 pump. The acquisition of this phenotype was posterior to the mdr-1 expressing phenotype since a HL60-DR5 variant, selected at the beginning of the induction of resistance, presented a low level of mdr-1 expression without resistance to apoptosis. The variations observed in the Fas (CD95) expression between sensitive and resistant cells were not sufficient to account for apoptosis resistance. However, a high expression in Abl antigen was found in all the apoptosis-resistant cells. RT-PCR and Western blot analysis showed that this increase in Abl antigen content was accompanied by the expression in U937-DR and HL60-DR100 cells of a hybrid bcr/abl mRNA and a 210 kD Bcr/Abl protein which was constitutive in K562. This expression was due to the translocation of abl and the amplification of the bcr-abl translocated gene. These results are in agreement with the role of Bcr/Abl tyrosine protein kinase as an inhibitor of apoptosis independently of the mdr-1 expression. They also suggest that translocation of the abl gene in the bcr region is a highly probable rearrangement in the mdr-1 expressing myeloid cells and that Bcr/Abl tyrosine kinase effect on apoptosis needs the regulation of intracellular pH and is inactive against UV-induced apoptosis.
authors.affiliation: Laboratoire d'Hématologie, Hôpital haut Lévêque, 33604 Pessac, France.
authors.forename: F
authors.initials: F
authors.lastname: Belloc
authors.forename: S
authors.initials: S
authors.lastname: Cotteret
authors.forename: G
authors.initials: G
authors.lastname: Labroille
authors.forename: V
authors.initials: V
authors.lastname: Schmit
authors.forename: C
authors.initials: C
authors.lastname: Jaloustre
authors.forename: P
authors.initials: P
authors.lastname: Dumain
authors.forename: F
authors.initials: F
authors.lastname: Durrieu
authors.forename: J
authors.initials: J
authors.lastname: Reiffers
authors.forename: M R
authors.initials: MR
authors.lastname: Boisseau
authors.forename: P
authors.initials: P
authors.lastname: Bernard
authors.forename: F
authors.initials: F
authors.lastname: Lacombe