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PMID:20855495

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Citation

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

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.

Links

PubMed PMC2947082 Online version:10.1084/jem.20100745

Keywords

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

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:TAL1

located_in

GO:0000785: chromatin

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:TAL1

involved_in

GO:0031334: positive regulation of protein-containing complex assembly

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:TAL1

enables

GO:0070888: E-box binding

ECO:0000314: direct assay evidence used in manual assertion

F

  • occurs_at:(SO:0001158)

Seeded From UniProt

complete

HUMAN:GATA3

located_in

GO:0000785: chromatin

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:GATA3

enables

GO:0070888: E-box binding

ECO:0000314: direct assay evidence used in manual assertion

F

  • occurs_at:(SO:0001158)

Seeded From UniProt

complete

HUMAN:RBTN1

involved_in

GO:0045944: positive regulation of transcription by RNA polymerase II

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:LDB1

located_in

GO:0000785: chromatin

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:LDB1

involved_in

GO:0045944: positive regulation of transcription by RNA polymerase II

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:NKX31

located_in

GO:0005634: nucleus

ECO:0000305: curator inference used in manual assertion

GO:0003700

C

Seeded From UniProt

complete

HUMAN:NKX31

enables

GO:0000976: transcription cis-regulatory region binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:TAL1

GO:0045931: positive regulation of mitotic cell cycle

ECO:0000315:

P

Tal-1 knockdown induced a partial blockage of the G2/M to G1 transition (Fig 1 b) and diminished uptake of BrdU in HSB2 cells indicated slow progression in S phase (Fig 1 c).

complete

HUMAN:TAL1

GO:0051781 : positive regulation of cell division

ECO:0000315:

P

Fig 1a (bottom). " TAL1 knockdown lengthend the doubling time of cells...".

complete

HUMAN:TAL1

part_of

GO:0000790: nuclear chromatin

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:TAL1

involved_in

GO:0031334: positive regulation of protein complex assembly

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:TAL1

involved_in

GO:0045799: positive regulation of chromatin assembly or disassembly

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:TAL1

involved_in

GO:0045931: positive regulation of mitotic cell cycle

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:TAL1

involved_in

GO:0045944: positive regulation of transcription by RNA polymerase II

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:TAL1

involved_in

GO:0051781: positive regulation of cell division

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:TAL1

enables

GO:0070888: E-box binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:GATA3

enables

GO:0070888: E-box binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:GATA3

involved_in

GO:0045944: positive regulation of transcription by RNA polymerase II

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:GATA3

part_of

GO:0000790: nuclear chromatin

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:NKX31

enables

GO:0003700: DNA-binding transcription factor activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:NKX31

part_of

GO:0005634: nucleus

ECO:0000305: curator inference used in manual assertion

GO:0003700

C

Seeded From UniProt

complete

HUMAN:NKX31

involved_in

GO:0051781: positive regulation of cell division

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:NKX31

involved_in

GO:0045944: positive regulation of transcription by RNA polymerase II

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:NKX31

enables

GO:0000976: transcription regulatory region sequence-specific DNA binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:NKX31

involved_in

GO:0045931: positive regulation of mitotic cell cycle

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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