NKX3.1 is a direct TAL1 target gene that mediates proliferation of TAL1-expressing human T cell acute lymphoblastic leukemia

Sophie Kusy; Bastien Gerby; Nicolas Goardon; Nathalie Gault; Federica Ferri; Delphine Gérard; Florence Armstrong; Paola Ballerini; Jean-Michel Cayuela; André Baruchel; Françoise Pflumio; Paul-Henri Roméo

doi:10.1084/jem.20100745

NKX3.1 is a direct TAL1 target gene that mediates proliferation of TAL1-expressing human T cell acute lymphoblastic leukemia

J Exp Med. 2010 Sep 27;207(10):2141-56. doi: 10.1084/jem.20100745. Epub 2010 Sep 20.

Authors

Sophie Kusy¹, Bastien Gerby, Nicolas Goardon, Nathalie Gault, Federica Ferri, Delphine Gérard, Florence Armstrong, Paola Ballerini, Jean-Michel Cayuela, André Baruchel, Françoise Pflumio, Paul-Henri Roméo

Affiliation

¹ Laboratoire de recherche sur la Réparation et la Transcription dans les cellules Souches, Direction des Sciences du Vivant, Commissariat à l'Energie Atomique et aux Energies Alternatives, 92265 Fontenay-aux-Roses, France.

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

Research Support, Non-U.S. Gov't

MeSH terms

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
T-Cell Acute Lymphocytic Leukemia Protein 1
Transcription Factors / genetics*
Transcription Factors / metabolism

Substances

Adaptor Proteins, Signal Transducing
Basic Helix-Loop-Helix Transcription Factors
DNA-Binding Proteins
GATA3 Transcription Factor
GATA3 protein, human
Homeodomain Proteins
LDB1 protein, human
LIM Domain Proteins
LMO1 protein, human
LMO2 protein, human
Metalloproteins
NKX3-1 protein, human
Proto-Oncogene Proteins
T-Cell Acute Lymphocytic Leukemia Protein 1
Transcription Factors
TAL1 protein, human