RNA polymerase II inhibitor, 5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole (DRB) causes erythroleukemic differentiation and transcriptional activation of erythroid genes.
Friend virus-transformed murine erythroleukemia (MEL) cells are a useful system for studying the regulation of erythroid growth and differentiation. As a manifestation of the leukemic process, these erythroblasts are blocked in their ability to terminally differentiate. However, this block is reversible as a variety of different agents are capable of inducing differentiation of these malignant erythroblasts. The mechanisms by which these agents cause differentiation remains unknown. We report here that 5,6-dichlorobenzimidazole (DRB), which inhibits RNA polymerase II by causing premature termination of transcription, induces differentiation of these cells, including the transcriptional activation of erythroid genes. The effects of DRB on nonerythroid gene expression and on cell growth are substantially different than that of the commonly used inducer, dimethyl sulfoxide (DMSO). The shared ability of DMSO, DRB, and other unrelated agents to induce erythroid gene expression in MEL cells while having differing effects on nonerythroid gene expression and on cell growth suggests that expression of the terminally differentiated phenotype represents a common pathway that can be triggered by different mechanisms.
Hensold
J O
JO
University/Ireland Cancer Center, Department of Medicine, Cleveland, Ohio, USA.
Barth
D
D
Stratton
C A
CA
D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism; D004004:Dichlororibofuranosylbenzimidazole / Q000494:pharmacology*; D004121:Dimethyl Sulfoxide / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004920:Erythropoiesis / Q000187:drug effects*; D005786:Gene Expression Regulation / Q000187:drug effects; D016259:Genes, myc; D005914:Globins / Q000235:genetics; D004915:Leukemia, Erythroblastic, Acute / Q000473:pathology; D051379:Mice; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D012319:RNA Polymerase II / Q000037:antagonists & inhibitors*; D012333:RNA, Messenger / Q000378:metabolism; D015534:Trans-Activators; D014158:Transcription, Genetic / Q000187:drug effects; D014407:Tumor Cells, Cultured; D000099232:Proto-Oncogene Protein Spi-1
D002868:Chromosomal Proteins, Non-Histone; D004004:Dichlororibofuranosylbenzimidazole; D004121:Dimethyl Sulfoxide; D004791:Enzyme Inhibitors; D005914:Globins; D011518:Proto-Oncogene Proteins; D012319:RNA Polymerase II; D012333:RNA, Messenger; D015534:Trans-Activators; D000099232:Proto-Oncogene Protein Spi-1; C030270:IP25 chromosomal protein, mouse