Williams-Beuren Syndrome Critical Region-5/Non-T Cell Activation Linker: A Novel Target Gene of AML1/ETO.
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AbstractThe chromosomal translocation (8;21) fuses the AML1 gene on chromosome 21 and the ETO gene on chromosome 8 in human acute myeloid leukemias, resulting in expression of the chimeric transcription factor AML1/ETO. AML1/ETO-mediated dysregulation of target genes critical for hematopoietic differentiation and proliferation is thought to contribute to the leukemic phenotype. Several mechanisms, including recruitment of histone deacetylases (HDACs) to AML1 target genes, may be responsible for altered gene expression. We used an ecdysone-inducible expression system in the human monoblastic U-937 cell line to isolate genes that were differentially expressed upon induction of AML1/ETO expression. By representational difference analysis (cDNA-RDA), we identified 26 genes whose expression levels were significantly modulated following AML1/ETO induction for 48 hours. None of these genes has previously been described as a target of AML1, ETO or AML1/ETO. One gene down-regulated by AML1/ETO in vitro, Williams Beuren Syndrome critical region 5 (WBSCR5), was expressed in primary t(8;21) negative AML blasts but not in primary t(8;21) positive AML blasts, strongly implying a role of this gene in the phenotype of t(8;21) positive AML. WBSCR5 is part of the critical region located on chromosome 7q11.23 that is deleted in the Williams Beuren syndrome (OMIM 194050), an autosomal dominant disorder comprising vascular, neurological, behavioral and skeletal abnormalities. WBSCR5 has recently been shown to have a role in the activation and differentiation of B cells (Brdicka et al., J. Exp. Med. 196:1617, 2002) and thus was also termed Non-T cell activation linker.. WBSCR5 as well as seven other regulated genes were further studied using all-trans-retinoic acid (ATRA), an inducer of differentiation of U-937 cells, and Trichostatin A (TSA), an HDAC inhibitor. WBSCR5 and two other out of these eight genes were regulated during ATRA-induced monocytic differentiation of U-937 cells, however none of them antagonistically, upon both ATRA-treatment and AML1/ETO-induction. Since repression of WBSCR5 might be mediated by recruitment of HDACs through the fusion gene, cells were treated with TSA prior to transgene induction. However, the AML1/ETO-associated dysregulation of WBSCR5 gene expression (as well as that of the other seven genes studied) was not mediated by a TSA-sensitive mechanism. The identified genes provide a useful model to study the mechanism by which the AML1/ETO fusion protein exerts its function in transcriptional dysregulation in acute myeloid leukemia. The role of WBSCR5 in malignant hematopoietic cells warrants further study.
