Journal
JOURNAL OF EXPERIMENTAL MEDICINE
Volume 207, Issue 10, Pages 2141-2156Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20100745
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Funding
- Commissariat a l'Energie Atomique et aux Energies Alternatives
- Association pour la Recherche sur le Cancer (ARC)
- Ligue Nationale contre le Cancer (LNCC)
- Societe Francaise d'Hematologie
- Domaine Interet Majeur Stem Pole
- Centre de Ressources de Modeles Experimentaux de Cancer
- Institut National de la Sante et de la Recherche Medicale
- Association Laurette Fugain
- Institut National du Cancer
- Canceropole Ile de France
- Agence Nationale pour la Recherche
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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-alpha (heterochromatin protein 1 alpha) 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.
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