ICSBP/IRF-8 inhibits mitogenic activity of p210 Bcr/Abl in differentiating myeloid progenitor cells.
Interferon consensus sequence binding protein/interferon regulatory factor 8 (ICSBP/IRF-8) is a transcription factor that controls myeloid cell development. ICSBP-/- mice develop a chronic myelogenous leukemia (CML)-like syndrome. Several observations on patients and mouse models have implicated ICSBP in the pathogenesis of CML. In this paper, we investigated whether ICSBP modulates the growth-promoting activity of Bcr/Abl, the causal oncoprotein for CML. When transformed with p210 Bcr/Abl, ICSBP-/- myeloid progenitor cells lost growth factor dependence and grew in the absence of granulocyte-macrophage colony-stimulating factor. When ICSBP was ectopically expressed, Bcr/Abl-transformed cells underwent complete growth arrest and differentiated into mature, functional macrophages without inhibiting the kinase activity of Bcr/Abl. Providing a mechanistic basis for the growth arrest, ICSBP markedly repressed c-Myc messenger RNA (mRNA)-expression, a downstream target of Bcr/Abl. A further analysis with the ICSBP/estrogen receptor chimera showed that ICSBP repression of c-Myc is indirect and is mediated by another gene(s). We identified Blimp-1 and METS/PE1, potent c-Myc repressors, as direct targets of ICSBP activated in these cells. Consistent with this, ectopic Blimp-1 repressed c-Myc expression and inhibited cell growth. These results indicate that ICSBP inhibits growth of Bcr/Abl-transformed myeloid progenitor cells by activating several genes that interfere with the c-Myc pathway.
Tamura
Tomohiko
T
Bldg 6, Rm 2A01, Laboratory of Molecular Growth Regulation, National Institute of Child Health and Human Development, National Institutes of Health, 6 Center Dr MSC 2753, Bethesda, MD 20892-2753, USA.
Kong
Hee Jeong
HJ
Tunyaplin
Chainarong
C
Tsujimura
Hideki
H
Calame
Kathryn
K
Ozato
Keiko
K
D000818:Animals; D001549:Benzamides; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured / Q000166:cytology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004958:Estradiol / Q000494:pharmacology; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors*; D005786:Gene Expression Regulation; D016259:Genes, myc; D000068877:Imatinib Mesylate; D050835:Interferon Regulatory Factors; D008264:Macrophages / Q000166:cytology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000166:cytology* / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology; D000074462:Positive Regulatory Domain I-Binding Factor 1; D011743:Pyrimidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D011960:Receptors, Estrogen / Q000187:drug effects / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000502:physiology; D012097:Repressor Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D014158:Transcription, Genetic; D000099185:Interferon Regulatory Factor-8
D001549:Benzamides; D004791:Enzyme Inhibitors; D004958:Estradiol; D016044:Fusion Proteins, bcr-abl; D000068877:Imatinib Mesylate; D050835:Interferon Regulatory Factors; D010879:Piperazines; D000074462:Positive Regulatory Domain I-Binding Factor 1; D011743:Pyrimidines; D012333:RNA, Messenger; D011960:Receptors, Estrogen; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; D000099185:Interferon Regulatory Factor-8; C412319:ETV3 protein, mouse; C513258:Prdm1 protein, mouse