AML1/ETO induces self-renewal in hematopoietic progenitor cells via the Groucho-related amino-terminal AES protein.
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.
Department of Medicine, Hematology and Oncology, University of Münster, Münster, Germany.
Björn
B
Steffen
Markus
M
Knop
Ulla
U
Bergholz
Olesya
O
Vakhrusheva
Miriam
M
Rode
Gabriele
G
Köhler
Marcel-Philipp
MP
Henrichs
Etmar
E
Bulk
Sina
S
Hehn
Martin
M
Stehling
Martin
M
Dugas
Nicole
N
Bäumer
Petra
P
Tschanter
Christian
C
Brandts
Steffen
S
Koschmieder
Wolfgang E
WE
Berdel
Hubert
H
Serve
Carol
C
Stocking
Carsten
C
Müller-Tidow
D000818:Animals; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D056970:Co-Repressor Proteins; D015972:Gene Expression Regulation, Neoplastic; D006367:HeLa Cells; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D000075142:RUNX1 Translocation Partner 1 Protein; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*
D056970:Co-Repressor Proteins; D011518:Proto-Oncogene Proteins; D000075142:RUNX1 Translocation Partner 1 Protein; C082222:RUNX1T1 protein, human; D012097:Repressor Proteins; C498445:TLE5 protein, human; D014157:Transcription Factors