Translocation Products in Acute Myeloid Leukemia Activate the Wnt Signaling Pathway in Hematopoietic Cells

Carsten Müller-Tidow, Björn Steffen, Thomas Cauvet, Lara Tickenbrock, Ping Ji, Sven Diederichs, Bülent Sargin, Gabriele Köhler, Matthias Stelljes, Elena Puccetti, Martin Ruthardt, Sven DeVos, Scott W. Hiebert, H. Phillip Koeffler, Wolfgang E. Berdel, Hubert Serve

Research output: Contribution to journalArticle

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Abstract

The acute myeloid leukemia (AML)-associated translocation products AML1-ETO, PML-retinoic acid receptor alpha (RARα), and PLZF-RARα 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-RARα, or PLZF-RARα. 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 (γ-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. β-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.

Original languageEnglish (US)
Pages (from-to)2890-2904
Number of pages15
JournalMolecular and Cellular Biology
Volume24
Issue number7
DOIs
StatePublished - Apr 2004
Externally publishedYes

Fingerprint

gamma Catenin
Wnt Signaling Pathway
Acute Myeloid Leukemia
Catenins
Proteins
Genes
Core Binding Factor alpha Subunits
Growth
Co-Repressor Proteins
U937 Cells
Histone Deacetylases
Cyclin D1
Myeloid Cells
Hematopoietic Stem Cells
Oligonucleotide Array Sequence Analysis
Transcriptional Activation
Transfection
Leukemia
Transcription Factors
Cell Proliferation

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cell Biology

Cite this

Translocation Products in Acute Myeloid Leukemia Activate the Wnt Signaling Pathway in Hematopoietic Cells. / Müller-Tidow, Carsten; Steffen, Björn; Cauvet, Thomas; Tickenbrock, Lara; Ji, Ping; Diederichs, Sven; Sargin, Bülent; Köhler, Gabriele; Stelljes, Matthias; Puccetti, Elena; Ruthardt, Martin; DeVos, Sven; Hiebert, Scott W.; Koeffler, H. Phillip; Berdel, Wolfgang E.; Serve, Hubert.

In: Molecular and Cellular Biology, Vol. 24, No. 7, 04.2004, p. 2890-2904.

Research output: Contribution to journalArticle

Müller-Tidow, C, Steffen, B, Cauvet, T, Tickenbrock, L, Ji, P, Diederichs, S, Sargin, B, Köhler, G, Stelljes, M, Puccetti, E, Ruthardt, M, DeVos, S, Hiebert, SW, Koeffler, HP, Berdel, WE & Serve, H 2004, 'Translocation Products in Acute Myeloid Leukemia Activate the Wnt Signaling Pathway in Hematopoietic Cells', Molecular and Cellular Biology, vol. 24, no. 7, pp. 2890-2904. https://doi.org/10.1128/MCB.24.7.2890-2904.2004
Müller-Tidow, Carsten ; Steffen, Björn ; Cauvet, Thomas ; Tickenbrock, Lara ; Ji, Ping ; Diederichs, Sven ; Sargin, Bülent ; Köhler, Gabriele ; Stelljes, Matthias ; Puccetti, Elena ; Ruthardt, Martin ; DeVos, Sven ; Hiebert, Scott W. ; Koeffler, H. Phillip ; Berdel, Wolfgang E. ; Serve, Hubert. / Translocation Products in Acute Myeloid Leukemia Activate the Wnt Signaling Pathway in Hematopoietic Cells. In: Molecular and Cellular Biology. 2004 ; Vol. 24, No. 7. pp. 2890-2904.
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AU - Ji, Ping

AU - Diederichs, Sven

AU - Sargin, Bülent

AU - Köhler, Gabriele

AU - Stelljes, Matthias

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AU - Ruthardt, Martin

AU - DeVos, Sven

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