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.
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.
Dayyani
Farshid
F
Department of Pediatrics, Division of Pediatric Hematology/Oncology, Massachusetts General Hospital, and Harvard Medical School, Boston, MA 02114, USA.
Wang
Jianfeng
J
Yeh
Jing-Ruey J
JR
Ahn
Eun-Young
EY
Tobey
Erica
E
Zhang
Dong-Er
DE
Bernstein
Irwin D
ID
Peterson
Randall T
RT
Sweetser
David A
DA
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
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