Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing
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Animals
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Basic Helix-Loop-Helix Transcription Factors / biosynthesis
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Basic Helix-Loop-Helix Transcription Factors / genetics*
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Cell Line, Tumor
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Cell Proliferation
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DNA-Binding Proteins / metabolism
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GATA3 Transcription Factor / metabolism
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Gene Knockdown Techniques
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Genes, Tumor Suppressor
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Homeodomain Proteins / genetics*
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Homeodomain Proteins / metabolism
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Humans
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LIM Domain Proteins
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Male
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Metalloproteins / metabolism
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Mice
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Neoplasm Transplantation
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Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / genetics*
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Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / metabolism
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Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / pathology
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Prostate / metabolism
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Prostate / pathology
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Protein Binding
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Proto-Oncogene Proteins / biosynthesis
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Proto-Oncogene Proteins / genetics*
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Stem Cells / physiology
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T-Cell Acute Lymphocytic Leukemia Protein 1
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Transcription Factors / genetics*
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Transcription Factors / metabolism
Substances
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Adaptor Proteins, Signal Transducing
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Basic Helix-Loop-Helix Transcription Factors
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DNA-Binding Proteins
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GATA3 Transcription Factor
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GATA3 protein, human
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Homeodomain Proteins
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LDB1 protein, human
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LIM Domain Proteins
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LMO1 protein, human
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LMO2 protein, human
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Metalloproteins
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NKX3-1 protein, human
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Proto-Oncogene Proteins
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T-Cell Acute Lymphocytic Leukemia Protein 1
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Transcription Factors
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TAL1 protein, human