Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
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SHR Neuro Krebs Kardio Lipid Stoffw Microb
Fisser, MC; Rommer, A; Steinleitner, K; Heller, G; Herbst, F; Wiese, M; Glimm, H; Sill, H; Wieser, R.
Induction of the proapoptotic tumor suppressor gene Cell Adhesion Molecule 1 by chemotherapeutic agents is repressed in therapy resistant acute myeloid leukemia.
Mol Carcinog. 2015; 54(12):1815-1819
Doi: 10.1002/mc.22252
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- Co-Autor*innen der Med Uni Graz
- Sill Heinz
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- Abstract:
- Even though a large proportion of patients with acute myeloid leukemia (AML) achieve a complete remission upon initial therapy, the majority of them eventually relapse with resistant disease. Overexpression of the gene coding for the transcription factor Ecotropic Virus Integration site 1 (EVI1) is associated with rapid disease recurrence and shortened survival. We therefore sought to identify EVI1 target genes that may play a role in chemotherapy resistance using a previously established in vitro model system for EVI1 positive myeloid malignancies. Gene expression microarray analyses uncovered the Cell Adhesion Molecule 1 (CADM1) gene as a candidate whose deregulation by EVI1 may contribute to drug refractoriness. CADM1 is an apoptosis inducing tumor suppressor gene that is inactivated by methylation in a variety of tumor types. In the present study we provide evidence that it may play a role in chemotherapy induced cell death in AML: CADM1 was induced by drugs used in the treatment of AML in a human myeloid cell line and in primary diagnostic AML samples, and its experimental expression in a cell line model increased the proportion of apoptotic cells. CADM1 up-regulation was abolished by ectopic expression of EVI1, and EVI1 expression correlated with increased CADM1 promoter methylation both in a cell line model and in primary AML cells. Finally, CADM1 induction was repressed in primary samples from AML patients at relapse. In summary, these data suggest that failure to up-regulate CADM1 in response to chemotherapeutic drugs may contribute to therapy resistance in AML. © 2014 The Authors. Molecular Carcinogenesis published by Wiley Periodicals, Inc.
- Find related publications in this database (using NLM MeSH Indexing)
- Aged -
- Antineoplastic Agents - pharmacology
- Apoptosis - drug effects
- Apoptosis - genetics
- Cell Adhesion Molecule-1 -
- Cell Adhesion Molecules - genetics
- Cell Line, Tumor -
- DNA Methylation - drug effects
- DNA Methylation - genetics
- DNA-Binding Proteins - genetics
- Drug Resistance, Neoplasm - genetics
- Female -
- Gene Expression - drug effects
- Gene Expression - genetics
- Genes, Tumor Suppressor - physiology
- Humans -
- Immunoglobulins - genetics
- Leukemia, Myeloid, Acute - drug therapy
- Leukemia, Myeloid, Acute - genetics
- MDS1 and EVI1 Complex Locus Protein -
- Middle Aged -
- Promoter Regions, Genetic - drug effects
- Promoter Regions, Genetic - genetics
- Proto-Oncogenes - genetics
- Transcription Factors - genetics
- Up-Regulation - drug effects
- Up-Regulation - genetics
- Find related publications in this database (Keywords)
- acute myeloid leukemia
- chemotherapy resistance
- relapse
- EVI1
- CADM1