title: Induction of the proapoptotic tumor suppressor gene Cell Adhesion Molecule 1 by chemotherapeutic agents is repressed in therapy resistant acute myeloid leukemia.
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.
authors.affiliation: Department of Medicine I, Medical University of Vienna, Vienna, Austria.|Comprehensive Cancer Center of the Medical University of Vienna, Vienna, Austria.
authors.forename: Muriel C
authors.initials: MC
authors.lastname: Fisser
authors.affiliation: Department of Medicine I, Medical University of Vienna, Vienna, Austria.|Comprehensive Cancer Center of the Medical University of Vienna, Vienna, Austria.
authors.forename: Anna
authors.initials: A
authors.lastname: Rommer
authors.affiliation: Department of Medicine I, Medical University of Vienna, Vienna, Austria.|Comprehensive Cancer Center of the Medical University of Vienna, Vienna, Austria.
authors.forename: Katarina
authors.initials: K
authors.lastname: Steinleitner
authors.affiliation: Department of Medicine I, Medical University of Vienna, Vienna, Austria.|Comprehensive Cancer Center of the Medical University of Vienna, Vienna, Austria.
authors.forename: Gerwin
authors.initials: G
authors.lastname: Heller
authors.affiliation: Department of Translational Oncology, National Center for Tumor Diseases (NCT) and German Cancer Research Center (DKFZ), Heidelberg, Germany.|German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany.
authors.forename: Friederike
authors.initials: F
authors.lastname: Herbst
authors.affiliation: Department of Translational Oncology, National Center for Tumor Diseases (NCT) and German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Meike
authors.initials: M
authors.lastname: Wiese
authors.affiliation: Department of Translational Oncology, National Center for Tumor Diseases (NCT) and German Cancer Research Center (DKFZ), Heidelberg, Germany.|German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany.
authors.forename: Hanno
authors.initials: H
authors.lastname: Glimm
authors.affiliation: Division of Hematology, Medical University of Graz, Graz, Austria.
authors.forename: Heinz
authors.initials: H
authors.lastname: Sill
authors.affiliation: Department of Medicine I, Medical University of Vienna, Vienna, Austria.|Comprehensive Cancer Center of the Medical University of Vienna, Vienna, Austria.
authors.forename: Rotraud
authors.initials: R
authors.lastname: Wieser
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics*; D000075982:Cell Adhesion Molecule-1; D015815:Cell Adhesion Molecules / Q000235:genetics*; D045744:Cell Line, Tumor; D019175:DNA Methylation / Q000187:drug effects / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics; D016147:Genes, Tumor Suppressor / Q000502:physiology*; D006801:Humans; D007136:Immunoglobulins / Q000235:genetics*; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics*; D000074008:MDS1 and EVI1 Complex Locus Protein; D008875:Middle Aged; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000235:genetics; D011519:Proto-Oncogenes / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; C403514:CADM1 protein, human; D000075982:Cell Adhesion Molecule-1; D015815:Cell Adhesion Molecules; D004268:DNA-Binding Proteins; D007136:Immunoglobulins; D000074008:MDS1 and EVI1 Complex Locus Protein; C063575:MECOM protein, human; D014157:Transcription Factors
keywords: CADM1; EVI1; acute myeloid leukemia; chemotherapy resistance; relapse