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

Abstract

The acute myeloid leukemia (AML)-associated translocation products AML1-ETO, PML-retinoic acid receptor alpha (RAR␣), and PLZF-RAR␣ 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-RAR␣, or PLZF-RAR␣. 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 (␥-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. ␤-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.

The role of TLE1 in synovial sarcoma

“…13 Although most of these related studies reported that the Groucho/TLE family of corepressors inhibits gene expression and the signaling pathway, it also enhances the gene expression including the macrophage colony stimulating factor receptor, 14 Notch ligand Jagged1, 15 and Wnt pathway mediator plakoglobin. 16 The Groucho/ TLE family of corepressors was also suggested to be an oncogene because the over-expression of Gro/TLE family members is associated with lung adenocarcinoma, 17 grade 1 astrocytomas, 18 higher-grade meningiomas, 19 pituitary adenomas, 20,21 and synovial sarcomas, 7,22 which is consistent with our results.…”

Oncogenic pathways of AML1-ETO in acute myeloid leukemia: Multifaceted manipulation of marrow maturation

“…Jagged upregulation triggered activation of the Notch pathway, and primary AML blasts with t(8;21) showed expression of the Notch target gene HES1. In a similar U937-based inducible system, Muller-Tidow and colleagues identified Plakoglobin as a target gene activated by AML1-ETO [21]. This upregulation occurred through direct transcriptional activation of the Plakoglobin promoter by AML1-ETO, a unique example of promoter activation by a putative transcriptional repressor.…”

Notch and Wnt signaling in T-lymphocyte development and acute lymphoblastic leukemia

“…Other reports indicate involvement of Wnt signaling in AML, CLL and multiple myeloma. [108][109][110][111] Studies on ALL are conspicuously absent, except for one report showing that the E2A-PBX1 fusion protein, involved in certain types of precursor B-ALL, activates the expression of Wnt16. 112 But studies with patient material and comparisons with normal precursor B cells (which undergo Wnt signaling) are lacking.…”