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 Blood, 15 April 2008, Vol. 111, No. 8, pp. 4338-4347.
Prepublished online as a Blood First Edition Paper on February 7, 2008; DOI 10.1182/blood-2007-07-103291.

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NEOPLASIA

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

Farshid Dayyani1,*, Jianfeng Wang1,*, Jing-Ruey J. Yeh2, Eun-Young Ahn3, Erica Tobey1, Dong-Er Zhang3, Irwin D. Bernstein4,5, Randall T. Peterson2, and David A. Sweetser1,4

1 Department of Pediatrics, Division of Pediatric Hematology/Oncology and 2 Cardiovascular Research Center and Cardiology Division, Massachusetts General Hospital, and Harvard Medical School, Boston, MA; 3 Department of Molecular and Experimental Medicine, Scripps Research Institute, La Jolla, CA, 4 Children's Oncology Group, Arcadia, CA; and 5 Department of Pediatric Oncology, Fred Hutchinson Cancer Research Center, Seattle, WA

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.


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