Effect of differentiation‐inducing agents on oncogene expression in a chronic myelogenous leukemia cell line

• Published in: Cancer 1988-09, Vol.62 (6), p.1171-1178
• Main Authors: Eisbruch, Avraham, Blick, Mark, Evinger‐Hodges, Mary Jeane, Beran, Miloslav, Andersson, Borje, Gutterman, Jordan U., Kurzrock, Razelle
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; Cell Differentiation - drug effects; Cell Division - drug effects; Cell Line; Fluorescent Antibody Technique; Hematologic and hematopoietic diseases; Hemin - pharmacology; Humans; Immunoenzyme Techniques; Leukemia, Myeloid - genetics; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Medical sciences; Models, Biological; Oncogenes - drug effects; RNA, Neoplasm - analysis
• ISSN: 0008-543X; 1097-0142
• DOI: 10.1002/1097-0142(19880915)62:6<1171::AID-CNCR2820620621>3.0.CO;2-8

K562 is a Philadelphia (Ph) chromosome‐positive chronic myelogenous leukemia (CML) blast crisis cell line representing a pluripotent precursor cell. At the molecular level, K562 cells express high levels of the aberrant bcr‐abl product, p210bcr‐abl, believed to be critical to the pathogenesis of CML. The authors demonstrate that exposure of K562 cells to hemin causes a state of partial, reversible erythroid maturation, accompanied by a marked decrease in p210bcr‐abl. The change in bcr‐abl expression may be mediated at the translational level since steady state amounts and enzymatic activity of the bcr‐abl protein are reduced whereas bcr‐abl mRNA levels are unaltered. The decrease in p210bcr‐abl phosphokinase enzymatic activity can be detected within 2 hours after addition of hemin to the culture media, indicating that changes in expression of this oncogene probably occur before or concurrent with differentiation. No change in bcr‐abl protein occurred in a CML cell line (KBM‐5) which did not undergo differentiation after exposure to hemin, consistent with a direct relationship between altered p210bcr‐abl expression and hemin‐induced erythroid differentiation. Importantly, the marked diminuition in bcr‐abl protein was not associated with a disruption in K562 growth rates, indicating that the proliferative capacity of these cells may be independent of the bcr‐abl product. In contrast to hemin, cytosine arabinoside (Ara‐C) caused terminal erythroid differentiation of K562 cells, characterized by irreversible hemoglobin accumulation and cytostasis; and no change in bcr‐abl protein expression was observed. The distinct effects of Ara‐C and hemin could reflect the existence of pleiotropic differentiation pathways. Both Ara‐C and hemin‐exposed cells showed a decrease in c‐myc and c‐myb transcripts, suggesting that altered levels of these proto‐oncogenes may be associated with erythroid maturation, regardless of the rate of cell division. K562 cells provide a useful model for analyzing the interaction between oncogene expression and CML cell growth and differentiation.