TLX Homeodomain Oncogenes Mediate T Cell Maturation Arrest in T-ALL via Interaction with ETS1 and Suppression of TCRα Gene Expression

被引：71

作者：

Dadi, Saida ^{[1
,3
]}

Le Noir, Sandrine ^{[1
]}

Payet-Bornet, Dominique ^{[3
]}

Lhermitte, Ludovic ^{[1
]}

Zacarias-Cabeza, Joaquin ^{[3
]}

Bergeron, Julie ^{[1
]}

Villarese, Patrick ^{[1
]}

Vachez, Elodie ^{[3
]}

Dik, Willem A. ^{[4
]}

Millien, Corinne ^{[1
]}

Radford, Isabelle ^{[2
]}

Verhoeyen, Els ^{[5
,6
,7
,8
]}

Cosset, Francois-Loic ^{[5
,6
,7
,8
]}

Petit, Arnaud ^{[9
]}

Ifrah, Norbert ^{[10
]}

Dombret, Herve ^{[11
]}

Hermine, Olivier ^{[1
]}

Spicuglia, Salvatore ^{[3
]}

Langerak, Anton W. ^{[4
]}

Macintyre, Elizabeth A. ^{[1
]}

Nadel, Bertrand ^{[3
]}

Ferrier, Pierre ^{[3
]}

Asnafi, Vahid ^{[1
]}

机构：

[1] Univ Med Paris Descartes Sorbonne Cite, CNRS, Hop Necker Enfants Malad, AP HP,Dept Hematol,UMR8147, F-75015 Paris, France

[2] Univ Paris 05, Hop Necker Enfants Malad, AP HP, Dept Cytogenet, F-75015 Paris, France

[3] Univ Aix Marseille 2, CNRS, INSERM, U1104,CIML,UMR7280, F-13009 Marseille, France

[4] Univ Med Ctr, Erasmus MC, Dept Immunol, NL-3016 Rotterdam, Netherlands

[5] Univ Lyon, F-69000 Lyon, France

[6] INSERM, U758, EVIR, Human Virol Dept, F-69007 Lyon, France

[7] Ecole Normale Super Lyon, F-69007 Lyon, France

[8] Univ Lyon 1, F-69007 Lyon, France

[9] Hop Armand Trousseau, AP HP, Dept Hematol, F-75012 Paris, France

[10] Ctr Hosp, Dept Hematol, F-49933 Angers, France

[11] Hop St Louis, AP HP, Dept Hematol, F-75010 Paris, France

来源：

CANCER CELL | 2012年 / 21卷 / 04期

关键词：

ACUTE LYMPHOBLASTIC-LEUKEMIA; PROTEIN-PROTEIN INTERACTIONS; DEVELOPMENTAL REGULATION; HISTONE ACETYLATION; V(D)J RECOMBINATION; LINEAGE COMMITMENT; ALLELIC EXCLUSION; VDJ RECOMBINATION; ALPHA/DELTA LOCUS; DELTA ENHANCER;

D O I：

10.1016/j.ccr.2012.02.013

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页码：563 / 576

页数：14

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