AML1/ETO induces self-renewal in hematopoietic progenitor cells via the Groucho-related amino-terminal AES protein.

Steffen B, Knop M, Bergholz U, Vakhrusheva O, Rode M, Köhler G, Henrichs MP, Bulk E, Hehn S, Stehling M, Dugas M, Bäumer N, Tschanter P, Brandts C, Koschmieder S, Berdel WE, Serve H, Stocking C, Müller-Tidow C

Research article (journal) | Peer reviewed

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.

Details about the publication

JournalBlood (Blood)
Volume117
Issue16
Page range4328-4337
StatusPublished
Release year2011
Language in which the publication is writtenEnglish
DOI10.1182/blood-2009-09-242545
KeywordsHematopoietic Stem Cells; Mice Inbred C57BL. Cells Cultured; Humans; Mice; Proto-Oncogene Proteins; Cell Line Tumor; Transcription Factors; Leukemia Myeloid Acute; Animals; Gene Expression Regulation Neoplastic; Repressor Proteins; Mice Inbred BALB C. HeLa Cells; Hematopoietic Stem Cells; Mice Inbred C57BL. Cells Cultured; Humans; Mice; Proto-Oncogene Proteins; Cell Line Tumor; Transcription Factors; Leukemia Myeloid Acute; Animals; Gene Expression Regulation Neoplastic; Repressor Proteins; Mice Inbred BALB C. HeLa Cells

Authors from the University of Münster

Bäumer, Nicole
Medical Clinic of Internal Medicine A (Hematology, Oncology, and Oneumology) (Med A)
Dugas, Martin
Institute of Medical Informatics
Köhler, Gabriele
Gerhard Domagk Institute of Pathology