AML1/ETO induces self-renewal in hematopoietic progenitor cells via the Groucho-related amino-terminal AES protein
| Autor: | Miriam Rode, Carol Stocking, Hubert Serve, Ulla Bergholz, Sina Hehn, Steffen Koschmieder, Martin Stehling, Nicole Bäumer, Marcel-Philipp Henrichs, Wolfgang E. Berdel, Markus Knop, Gabriele Köhler, Martin Dugas, Carsten Müller-Tidow, Björn Steffen, Olesya Vakhrusheva, Etmar Bulk, Christian Brandts, Petra Tschanter |
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| Rok vydání: | 2011 |
| Předmět: |
Immunology
Chromosomal translocation Biology Biochemistry Mice RUNX1 Translocation Partner 1 Protein RNA interference Cell Line Tumor Proto-Oncogene Proteins hemic and lymphatic diseases medicine Animals Humans Progenitor cell neoplasms Cells Cultured Mice Inbred BALB C Gene knockdown Myeloid leukemia Cell Biology Hematology Hematopoietic Stem Cells medicine.disease Molecular biology Gene Expression Regulation Neoplastic Mice Inbred C57BL Repressor Proteins Leukemia Myeloid Acute Leukemia Cell culture Stem cell Co-Repressor Proteins HeLa Cells Transcription Factors |
| Zdroj: | Blood. 117:4328-4337 |
| ISSN: | 1528-0020 0006-4971 |
| DOI: | 10.1182/blood-2009-09-242545 |
| Popis: | The most frequent translocation t(8;21) in acute myeloid leukemia (AML) generates the chimeric AML1/ETO protein, which blocks differentiation and induces self-renewal in hematopoietic progenitor cells. The underlying mechanisms mediating AML1/ETO-induced self-renewal are largely unknown. Using expression microarray analysis, we identified the Groucho-related amino-terminal enhancer of split (AES) as a consistently up-regulated AML1/ETO target. Elevated levels of AES mRNA and protein were confirmed in AML1/ETO-expressing leukemia cells, as well as in other AML specimens. High expression of AES mRNA or protein was associated with improved survival of AML patients, even in the absence of t(8;21). On a functional level, knockdown of AES by RNAi in AML1/ETO-expressing cell lines inhibited colony formation. Similarly, self-renewal induced by AML1/ETO in primary murine progenitors was inhibited when AES was decreased or absent. High levels of AES expression enhanced formation of immature colonies, serial replating capacity of primary cells, and colony formation in colony-forming unit-spleen assays. These findings establish AES as a novel AML1/ETO-induced target gene that plays an important role in the self-renewal phenotype of t(8;21)-positive AML. |
| Databáze: | OpenAIRE |
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