Functional analyses of the TEL-ARNT fusion protein underscores a role for oxygen tension in hematopoietic cellular differentiation

• Published in: Oncogene Vol. 25; no. 35; pp. 4840 - 4847
• Main Authors: NGUYEN-KHAC, F, DELLA VALLE, V, LOPEZ, R. G, RAVET, E, MAUCHAUFFE, M, FRIEDMAN, A. D, HUANG, L. E, FICHELSON, S, GHYSDAEL, J, BERNARD, O. A
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing 10.08.2006; Nature Publishing Group
• Subjects: Acute myeloid leukemia; Animals; Aryl Hydrocarbon Receptor Nuclear Translocator - genetics; Aryl Hydrocarbon Receptor Nuclear Translocator - physiology; Biological and medical sciences; CD34 antigen; Cell differentiation; Cell Differentiation - genetics; Cell differentiation, maturation, development, hematopoiesis; Cell Line; Cell physiology; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Chromosome translocations; Colony-stimulating factor; ETS protein; ETS Translocation Variant 6 Protein; Fundamental and applied biological sciences. Psychology; Fusion protein; Gene expression; Genes; Granulocyte colony-stimulating factor; HeLa Cells; Hematologic and hematopoietic diseases; Hematopoiesis - genetics; Hemopoiesis; Humans; Hypoxia; Hypoxia-inducible factor 1; Leukemia; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Leukocytes (granulocytic); Medical sciences; Mice; Molecular and cellular biology; Myeloblastic leukemia; Myeloid cells; Oxygen; Oxygen - blood; Oxygen tension; Progenitor cells; Proteins; Proto-Oncogene Proteins c-ets - genetics; Proto-Oncogene Proteins c-ets - physiology; Recombinant Fusion Proteins - genetics; Recombinant Fusion Proteins - physiology; Repressor Proteins - genetics; Repressor Proteins - physiology; Stem cells; Oxygen; TEL/ETV6; Hematopoiesis; Analysis; Leukemia; ARNT; Malignant hemopathy; differentiation block; Differentiation; Transcription factor; Fusion protein; Carcinogenesis
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/sj.onc.1209503

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.