Analysis of genes under the downstream control of the t(8;21) fusion protein AML1-MTG8: overexpression of the TIS11b (ERF-1, cMG1) gene induces myeloid cell proliferation in response to G-CSF

The AML1-MTG8 fusion transcription factor generated by t(8;21) translocatio n is thought to dysregulate genes that are crucial for normal differentiati on and proliferation of hematopoietic progenitors to cause acute myelogenou s leukemia (AML), Although AML1-MTG8 has been shown to repress the transcri ption of AML1 targets, none of the known targets of AML1 are probably respo nsible for AML1-MTG8-mediated leukemogenesis. In this study, 24 genes under the downstream control of AML1-MTG8 were isolated by using a differential display technique, Analysis with deletion mutants of AML1-MTG8 demonstrated that the regulation of the majority of these genes requires the region of 51 residues (488-538) containing the Nervy homology region 2 (NHR2), throug h which AML1-MTG8 interacts with MTGR1, Among the 24 genes identified, 10 w ere considered to be genes under the control of AML1, because their express ion was altered by AML1b or AML1a or both. However, the other 14 genes were not affected by either AML1b or AML1a, suggesting the possibility that AML 1-MTG8 regulates a number of specific target genes that are not normally re gulated by AML1, Furthermore, an up-regulated gene, TIS11b (ERF-1, cMG1), w as highly expressed in t(8;21) leukemic cells, and the overexpression of TI S11b induced myeloid cell proliferation in response to granulocyte colony-s timulating factor. These results suggest that the high-level expression of TIS11b contributes to AML1-MTG8-mediated leukemogenesis, (C) 2000 by The Am erican Society of Hematology.