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
Copyright policy )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
AbstractDeletions 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.
- Scripps Research Institute United States
- Harvard University United States
- Fred Hutchinson Cancer Research Center United States
- Massachusetts General Hospital United States
- Children's Oncology Group Switzerland
Embryo, Nonmammalian, Cell Death, Oncogene Proteins, Fusion, Cell Survival, Chromosomes, Human, Pair 21, Nuclear Proteins, DNA-Binding Proteins, Leukemia, Myeloid, Acute, Phenotype, RUNX1 Translocation Partner 1 Protein, Cell Line, Tumor, Core Binding Factor Alpha 2 Subunit, Animals, Humans, Myeloid Cells, Co-Repressor Proteins, Gene Deletion, Cell Proliferation, Chromosomes, Human, Pair 8, Protein Binding
Embryo, Nonmammalian, Cell Death, Oncogene Proteins, Fusion, Cell Survival, Chromosomes, Human, Pair 21, Nuclear Proteins, DNA-Binding Proteins, Leukemia, Myeloid, Acute, Phenotype, RUNX1 Translocation Partner 1 Protein, Cell Line, Tumor, Core Binding Factor Alpha 2 Subunit, Animals, Humans, Myeloid Cells, Co-Repressor Proteins, Gene Deletion, Cell Proliferation, Chromosomes, Human, Pair 8, Protein Binding
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