Translocation products in acute myeloid leukemia activate the Wnt signaling pathway in hematopoietic cells.
The acute myeloid leukemia (AML)-associated translocation products AML1-ETO, PML-retinoic acid receptor alpha (RARalpha), and PLZF-RARalpha encode aberrant transcription factors. Several lines of evidence suggest similar pathogenetic mechanisms for these fusion proteins. We used high-density oligonucleotide arrays to identify shared target genes in inducibly transfected U937 cells expressing AML1-ETO, PML-RARalpha, or PLZF-RARalpha. All three fusion proteins significantly repressed the expression of 38 genes and induced the expression of 14 genes. Several of the regulated genes were associated with Wnt signaling. One of these, plakoglobin (gamma-catenin), was induced on the mRNA and protein level by all three fusion proteins. In addition, primary AML blasts carrying one of the fusion proteins significantly overexpressed plakoglobin. The plakoglobin promoter was cloned and shown to be induced by AML1-ETO, with promoter activation depending on the corepressor and histone deacetylase binding domains. The induction of plakoglobin by AML fusion proteins led to downstream signaling and transactivation of TCF- and LEF-dependent promoters, including the c-myc promoter, which was found to be bound by plakoglobin in vivo after AML1-ETO expression. beta-Catenin protein levels and TCF and LEF target genes such as c-myc and cyclin D1 were found to be induced by the fusion proteins. On the functional level, a dominant negative TCF inhibited colony growth of AML1-ETO-positive Kasumi cells, whereas plakoglobin transfection into myeloid 32D cells enhanced proliferation and clonal growth. Injection of plakoglobin-expressing 32D cells into syngeneic mice accelerated the development of leukemia. Transduction of plakoglobin into primitive murine hematopoietic progenitor cells preserved the immature phenotype during colony growth, suggesting enhanced self-renewal. These data provide evidence that activation of Wnt signaling is a common feature of several balanced translocations in AML.
Müller-Tidow
Carsten
C
Department of Medicine, Gerhard Domagk Institute of Pathology, University of Münster, Münster, Germany. muellerc@uni-muenster.de
Steffen
Björn
B
Cauvet
Thomas
T
Tickenbrock
Lara
L
Ji
Ping
P
Diederichs
Sven
S
Sargin
Bülent
B
Köhler
Gabriele
G
Stelljes
Matthias
M
Puccetti
Elena
E
Ruthardt
Martin
M
deVos
Sven
S
Hiebert
Scott W
SW
Koeffler
H Phillip
HP
Berdel
Wolfgang E
WE
Serve
Hubert
H
D000818:Animals; D045744:Cell Line, Tumor; D050676:Core Binding Factor Alpha 2 Subunit; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D051180:Desmoplakins; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006412:Hematopoietic Stem Cells / Q000502:physiology*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051821:Lymphoid Enhancer-Binding Factor 1; D051379:Mice; D008810:Mice, Inbred C57BL; D009363:Neoplasm Proteins / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D015514:Oncogene Proteins, Fusion / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D000075142:RUNX1 Translocation Partner 1 Protein; D015398:Signal Transduction / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014185:Transplantation, Isogeneic; D051153:Wnt Proteins; D029961:Zebrafish Proteins; D051185:gamma Catenin
C107844:AML1-ETO fusion protein, human; D050676:Core Binding Factor Alpha 2 Subunit; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; D051180:Desmoplakins; C111931:ELF4 protein, human; C491779:Elf4 protein, mouse; C495292:JUP protein, human; C495293:Jup protein, mouse; D051821:Lymphoid Enhancer-Binding Factor 1; D009363:Neoplasm Proteins; D015514:Oncogene Proteins, Fusion; C118318:PLZF-RARalpha fusion protein, human; C492209:PLZF-RARalpha fusion protein, mouse; D011518:Proto-Oncogene Proteins; D000075142:RUNX1 Translocation Partner 1 Protein; D014157:Transcription Factors; D051153:Wnt Proteins; D029961:Zebrafish Proteins; D051185:gamma Catenin; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein