NKX3.1 is a direct TAL1 target gene that mediates proliferation of TAL1-expressing human T cell acute lymphoblastic leukemia.
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.
Kusy
Sophie
S
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.
Gerby
Bastien
B
Goardon
Nicolas
N
Gault
Nathalie
N
Ferri
Federica
F
Gérard
Delphine
D
Armstrong
Florence
F
Ballerini
Paola
P
Cayuela
Jean-Michel
JM
Baruchel
André
A
Pflumio
Françoise
F
Roméo
Paul-Henri
PH
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000096:biosynthesis / Q000235:genetics*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004268:DNA-Binding Proteins / Q000378:metabolism; D050990:GATA3 Transcription Factor / Q000378:metabolism; D055785:Gene Knockdown Techniques; D016147:Genes, Tumor Suppressor; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D060588:LIM Domain Proteins; D008297:Male; D008667:Metalloproteins / Q000378:metabolism; D051379:Mice; D009368:Neoplasm Transplantation; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011467:Prostate / Q000378:metabolism / Q000473:pathology; D011485:Protein Binding; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics*; D013234:Stem Cells / Q000502:physiology; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D051792:Basic Helix-Loop-Helix Proteins; D004268:DNA-Binding Proteins; D050990:GATA3 Transcription Factor; D018398:Homeodomain Proteins; D060588:LIM Domain Proteins; D008667:Metalloproteins; D011518:Proto-Oncogene Proteins; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; D014157:Transcription Factors; C494749:GATA3 protein, human; C486312:LDB1 protein, human; C065072:LMO1 protein, human; C085117:LMO2 protein, human; C491178:NKX3-1 protein, human; C067143:TAL1 protein, human