Nguyen-Khac F, Della Valle V, Lopez R G, Ravet E, Mauchauffé M, Friedman A D, Huang L E, Fichelson S, Ghysdael J, Bernard O A
Service d'hématologie biologique, Groupe hospitalier Pitié-Salpêtrière, and E0210 INSERM, IRNEM, Université Paris V, Hôpital Necker, Paris, France.
Oncogene. 2006 Aug 10;25(35):4840-7. doi: 10.1038/sj.onc.1209503. Epub 2006 Mar 20.
The transcription factor hypoxia inducible factor 1 (HIF1), an HIF1alpha-aryl hydrocarbon receptor nuclear translocator (ARNT) dimeric factor, is essential to the cellular response to hypoxia. We described a t(1;12)(q21;p13) chromosomal translocation in human acute myeloblastic leukemia that involves the translocated Ets leukemia (TEL/ETV6) and the ARNT genes and results in the expression of a TEL-ARNT fusion protein. Functional studies show that TEL-ARNT interacts with HIF1alpha and the complex binds to consensus hypoxia response element. In low oxygen tension conditions, the HIF1alpha/TEL-ARNT complex does not activate transcription but exerts a dominant-negative effect on normal HIF1 activity. Differentiation of normal human CD34+ progenitors cells along all the erythrocytic, megakaryocytic and granulocytic pathways was accelerated in low versus high oxygen tension conditions. Murine 32Dcl3 myeloid cells also show accelerated granulocytic differentiation in low oxygen tension in response to granulocyte colony-stimulating factor. Interestingly, stable expression of the TEL-ARNT in 32Dcl3 subclones resulted in impaired HIF1-mediated transcriptional response and inhibition of differentiation enhancement in hypoxic conditions. Taken together, our results underscore the role of oxygen tension in the modulation of normal hematopoietic differentiation, whose targeting can participate in human malignancies.
转录因子缺氧诱导因子1（HIF1）是一种由HIF1α-芳烃受体核转运蛋白（ARNT）组成的二聚体因子，对细胞对缺氧的反应至关重要。我们描述了人类急性髓细胞白血病中的一种t(1;12)(q21;p13)染色体易位，该易位涉及易位的Ets白血病（TEL/ETV6）和ARNT基因，并导致TEL-ARNT融合蛋白的表达。功能研究表明，TEL-ARNT与HIF1α相互作用，且该复合物与共有缺氧反应元件结合。在低氧张力条件下，HIF1α/TEL-ARNT复合物不激活转录，而是对正常的HIF1活性发挥显性负效应。与高氧张力条件相比，在低氧张力条件下，正常人CD34+祖细胞沿所有红细胞、巨核细胞和粒细胞途径的分化加速。小鼠32Dcl3髓样细胞在低氧张力下对粒细胞集落刺激因子也表现出加速的粒细胞分化。有趣的是，TEL-ARNT在32Dcl3亚克隆中的稳定表达导致HIF1介导的转录反应受损，并在缺氧条件下抑制分化增强。综上所述，我们的结果强调了氧张力在调节正常造血分化中的作用，其靶向作用可能参与人类恶性肿瘤的发生。
