Intraclonal heterogeneity in the in vitro daunorubicin-induced apoptosis in acute myeloid leukemia.
Leukemic cells from ten patients with acute myeloid leukemia (AML) were sorted on the basis of in vitro daunorubicin (DNR) uptake. The obtained subpopulations with high and low DNR accumulation were compared with regard to induction of apoptosis, expression of bcl-2 and p53. Heterogeneous induction of apoptosis, confined to subpopulations with high DNR uptake, was observed. The size of the DNR-induced apoptotic fraction (4% to 16%) within a given AML blast population was determined by intracellular drug accumulation and was not related to the level of bcl-2 expression. All tested leukemic samples displayed expression of p53 in a growth promoter orientation, i.e. PAb1620-/PAb240+. In two samples, however, subpopulations expressing a growth suppressor orientation of p53, i.e. PAb 1620+/PAb240-, were also present. These subpopulations were confined to high-DNR-uptake fractions and associated with the induction of apoptosis. We conclude that intraclonal heterogeneity in the intracellular drug accumulation and subsequently in DNR-induced apoptosis might allow the selection of inherently drug-resistant AML clones thus contributing to relapse of leukemia.
Department of Hematology and Infection, Karolinska Hospital, Stockholm, Sweden.
K A
KA
Palucka
E
E
Knaust
D
D
Xu
B
B
Macnamara
A
A
Porwit-Macdonald
A
A
Gruber
C
C
Peterson
M
M
Björkholm
P
P
Pisa
D000208:Acute Disease; D017209:Apoptosis / Q000187:drug effects*; D002469:Cell Separation; D002999:Clone Cells / Q000187:drug effects / Q000473:pathology; D003630:Daunorubicin / Q000378:metabolism / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D006801:Humans; D007951:Leukemia, Myeloid / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis
D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D003630:Daunorubicin