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.

Publication Type:

Journal Article

Source:

Blood, Volume 111, Issue 8, p.4338-47 (2008)

Keywords:

2008, Animals, Cell Death, Cell Line, Tumor, Cell Proliferation, Cell Survival, Chromosomes, Human, Pair 21, Chromosomes, Human, Pair 8, Clinical Research Division, Core Binding Factor Alpha 2 Subunit, DNA-Binding Proteins, Embryo, Nonmammalian, Gene Deletion, Humans, Leukemia, Myeloid, Acute, Myeloid Cells, Nuclear Proteins, Oncogene Proteins, Fusion, PHENOTYPE, Protein Binding, Repressor Proteins, Translocation, Genetic, zebrafish, Zebrafish Proteins

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.