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AML1/ETO induces self-renewal in hematopoietic progenitor cells via the Groucho-related amino-terminal AES protein.
- Source :
-
Blood [Blood] 2011 Apr 21; Vol. 117 (16), pp. 4328-37. Date of Electronic Publication: 2011 Jan 18. - Publication Year :
- 2011
-
Abstract
- 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.
- Subjects :
- Animals
Cell Line, Tumor
Cells, Cultured
Co-Repressor Proteins
HeLa Cells
Hematopoietic Stem Cells metabolism
Hematopoietic Stem Cells pathology
Humans
Leukemia, Myeloid, Acute metabolism
Leukemia, Myeloid, Acute pathology
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
RUNX1 Translocation Partner 1 Protein
Repressor Proteins metabolism
Gene Expression Regulation, Neoplastic
Hematopoietic Stem Cells cytology
Leukemia, Myeloid, Acute genetics
Proto-Oncogene Proteins metabolism
Repressor Proteins genetics
Transcription Factors metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1528-0020
- Volume :
- 117
- Issue :
- 16
- Database :
- MEDLINE
- Journal :
- Blood
- Publication Type :
- Academic Journal
- Accession number :
- 21245488
- Full Text :
- https://doi.org/10.1182/blood-2009-09-242545