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Kusy, S, Gerby, B, Goardon, N, Gault, N, Ferri, F, Gérard, D, Armstrong, F, Ballerini, P, Cayuela, JM, Baruchel, A, Pflumio, F and Roméo, PH (2010) NKX3.1 is a direct TAL1 target gene that mediates proliferation of TAL1-expressing human T cell acute lymphoblastic leukemia. J. Exp. Med. 207:2141-56
TAL1 (also known as SCL) is expressed in >40% of human T cell acute lymphoblastic leukemias (T-ALLs). TAL1 encodes a basic helix-loop-helix transcription factor that can interfere with the transcriptional activity of E2A and HEB during T cell leukemogenesis; however, the oncogenic pathways directly activated by TAL1 are not characterized. In this study, we show that, in human TAL1-expressing T-ALL cell lines, TAL1 directly activates NKX3.1, a tumor suppressor gene required for prostate stem cell maintenance. In human T-ALL cell lines, NKX3.1 gene activation is mediated by a TAL1-LMO-Ldb1 complex that is recruited by GATA-3 bound to an NKX3.1 gene promoter regulatory sequence. TAL1-induced NKX3.1 activation is associated with suppression of HP1-α (heterochromatin protein 1 α) binding and opening of chromatin on the NKX3.1 gene promoter. NKX3.1 is necessary for T-ALL proliferation, can partially restore proliferation in TAL1 knockdown cells, and directly regulates miR-17-92. In primary human TAL1-expressing leukemic cells, the NKX3.1 gene is expressed independently of the Notch pathway, and its inactivation impairs proliferation. Finally, TAL1 or NKX3.1 knockdown abrogates the ability of human T-ALL cells to efficiently induce leukemia development in mice. These results suggest that tumor suppressor or oncogenic activity of NKX3.1 depends on tissue expression.
Adaptor Proteins, Signal Transducing; Animals; Basic Helix-Loop-Helix Transcription Factors/biosynthesis; Basic Helix-Loop-Helix Transcription Factors/genetics; Cell Line, Tumor; Cell Proliferation; DNA-Binding Proteins/metabolism; GATA3 Transcription Factor/metabolism; Gene Knockdown Techniques; Genes, Tumor Suppressor; Homeodomain Proteins/genetics; Homeodomain Proteins/metabolism; Humans; LIM Domain Proteins; Male; Metalloproteins/metabolism; Mice; Neoplasm Transplantation; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/genetics; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/metabolism; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/pathology; Prostate/metabolism; Prostate/pathology; Protein Binding; Proto-Oncogene Proteins/biosynthesis; Proto-Oncogene Proteins/genetics; Stem Cells/physiology; Transcription Factors/genetics; Transcription Factors/metabolism