title: Loss of TLE1 and TLE4 from the del(9q) commonly deleted region in AML cooperates with AML1-ETO to affect myeloid cell proliferation and survival.
abstract: Deletions on chromosome 9q are seen in a subset of acute myeloid leukemia (AML) cases and are specifically associated with t(8;21) AML. We previously defined the commonly deleted region in del(9q) AML and characterized the genes in this interval. To determine the critical lost gene(s) that might cooperate with the AML1-ETO fusion gene produced by t(8;21), we developed a set of shRNAs directed against each gene in this region. Within this library, shRNAs to TLE1 and TLE4 were the only shRNAs capable of rescuing AML1-ETO expressing U937T-A/E cells from AML1-ETO-induced cell-cycle arrest and apoptosis. Knockdown of TLE1 or TLE4 levels increased the rate of cell division of the AML1-ETO-expressing Kasumi-1 cell line, whereas forced expression of either TLE1 or TLE4 caused apoptosis and cell death. Knockdown of Gro3, a TLE homolog in zebrafish, cooperated with AML1-ETO to cause an accumulation of noncirculating hematopoietic blast cells. Our data are consistent with a model in which haploinsufficiency of these TLEs overcomes the negative survival and antiproliferative effects of AML1-ETO on myeloid progenitors, allowing preleukemic stem cells to expand into AML. This study is the first to implicate the TLEs as potential tumor suppressor genes in myeloid leukemia.
authors.affiliation: Department of Pediatrics, Division of Pediatric Hematology/Oncology, Massachusetts General Hospital, and Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Farshid
authors.initials: F
authors.lastname: Dayyani
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Wang
authors.forename: Jing-Ruey J
authors.initials: JR
authors.lastname: Yeh
authors.forename: Eun-Young
authors.initials: EY
authors.lastname: Ahn
authors.forename: Erica
authors.initials: E
authors.lastname: Tobey
authors.forename: Dong-Er
authors.initials: DE
authors.lastname: Zhang
authors.forename: Irwin D
authors.initials: ID
authors.lastname: Bernstein
authors.forename: Randall T
authors.initials: RT
authors.lastname: Peterson
authors.forename: David A
authors.initials: DA
authors.lastname: Sweetser
mesh_terms: D000818:Animals; D016923:Cell Death; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D002891:Chromosomes, Human, Pair 21 / Q000235:genetics; D002898:Chromosomes, Human, Pair 8 / Q000235:genetics; D056970:Co-Repressor Proteins; D050676:Core Binding Factor Alpha 2 Subunit / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000172:deficiency*; D004625:Embryo, Nonmammalian / Q000378:metabolism; D017353:Gene Deletion; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics*; D022423:Myeloid Cells / Q000473:pathology*; D009687:Nuclear Proteins / Q000172:deficiency*; D015514:Oncogene Proteins, Fusion / Q000378:metabolism*; D010641:Phenotype; D011485:Protein Binding; D000075142:RUNX1 Translocation Partner 1 Protein; D012097:Repressor Proteins / Q000378:metabolism*; D014178:Translocation, Genetic; D015027:Zebrafish / Q000196:embryology; D029961:Zebrafish Proteins / Q000378:metabolism
chemical_list: C107844:AML1-ETO fusion protein, human; D056970:Co-Repressor Proteins; D050676:Core Binding Factor Alpha 2 Subunit; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D015514:Oncogene Proteins, Fusion; D000075142:RUNX1 Translocation Partner 1 Protein; D012097:Repressor Proteins; C499043:TLE1 protein, human; C465817:TLE4 protein, human; D029961:Zebrafish Proteins