Loss of TLE1 and TLE4 from the del(9q) commonly deleted region in AML cooperate with AML1-ETO to affect myeloid cell proliferation and survival

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 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, while forced expression of either TLE1 or TLE4 caused apoptosis and cell death. Knockdown of Gro3, a TLE homologue in zebrafish, cooperated with AML1-ETO to cause an accumulation of non-circulating hematopoietic blast cells. Our data is consistent with a model in which haploinsufficiency of these TLEs overcomes the negative survival and anti-proliferative effects of AML1-ETO on myeloid progenitors allowing preleukemic stem cells to expand into acute myeloid leukemia. This study is the first to implicate the TLEs as potential tumor suppressor genes in myeloid leukemia.