Journal
CANCER CELL
Volume 21, Issue 4, Pages 563-576Publisher
CELL PRESS
DOI: 10.1016/j.ccr.2012.02.013
Keywords
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Categories
Funding
- Dutch Childhood Oncology Group (DCOG) [OC2001/003]
- COG ALL [2002-09]
- Ministere de l'Enseignement Superieur et de la Recherche
- Fondation pour la Recherche Medicale (FRM)
- Societe Francaise d'Hematologie (SFH)
- Agence Nationale de la Fecherche (ANR)
- National Cancer Institute of Canada (NCIC)
- Terry Fox Foundation (TFF)
- Dutch Cancer Society [EMCR 2002-2707]
- Institut National du Cancer (INCa-DHOS)
- Association pour la Recherche sur le Cancer (ARC)
- ARC
- Fondation de France/Comite Leucemie and Enfants et Sante
- Societe Francaise de Lutte contre les Cancers et Leucemies de l'Enfant et de l'Adolescent (SFCE)
- Inserm
- CNRS
- Commission of the European Communities
- ANR
- INCa
- Fondation Princesse Grace de Monaco
- Fondation de France
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Acute lymphoblastic leukemias (ALLs) are characterized by multistep oncogenic processes leading to cell-differentiation arrest and proliferation. Specific abrogation of maturation blockage constitutes a promising therapeutic option in cancer, which requires precise understanding of the underlying molecular mechanisms. We show that the cortical thymic maturation arrest in T-lineage ALLs that overexpress TLX1 or TLX3 is due to binding of TLX1/TLX3 to ETS1, leading to repression of T cell receptor (TCR) alpha enhanceosome activity and blocked TCR-J alpha rearrangement. TLX1/TLX3 abrogation or enforced TCR alpha beta expression leads to TCR alpha rearrangement and apoptosis. Importantly, the autoextinction of clones carrying TCR alpha-driven TLX1 expression supports TLX addiction in TLX-positive leukemias and provides further rationale for targeted therapy based on disruption of TLX1/TLX3.
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