Induction of the proapoptotic tumor suppressor gene Cell Adhesion Molecule 1 by chemotherapeutic agents is repressed in therapy resistant acute myeloid leukemia. Issue 12 (9th December 2014)

• Record Type: Journal Article
• Authors: Fisser, Muriel C.; Rommer, Anna; Steinleitner, Katarina; Heller, Gerwin; Herbst, Friederike; Wiese, Meike; Glimm, Hanno; Sill, Heinz; Wieser, Rotraud
• Is Part Of: Molecular carcinogenesis. Volume 54:Issue 12(2015:Dec.)
• Page Start: 1815
• Page End: 1819
• Publication Date: 2014-12-09
• Subjects: Carcinogenesis -- Molecular aspects -- Periodicals; 616.994071
• DOI: 10.1002/mc.22252
• Languages: English
• ISSNs: 0899-1987

Abstract

<abstract abstract-type="main" xml:lang="en"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="mc22252-sec-0001" sec-type="section"> <p>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 (<italic>CADM1</italic>) gene as a candidate whose deregulation by EVI1 may contribute to drug refractoriness. <italic>CADM1</italic> 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: <italic>CADM1</italic> 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. <italic>CADM1</italic> up‐regulation was abolished by ectopic expression of EVI1, and EVI1 expression correlated with increased <italic>CADM1</italic> promoter methylation both in a cell line model and in primary AML cells. Finally, <italic>CADM1</italic> induction was repressed in primary samples from AML patients at relapse. In summary, these data suggest that failure to up‐regulate <italic>CADM1</italic> in response to chemotherapeutic drugs may contribute to therapy resistance in AML. © 2014 The Authors. <italic>Molecular Carcinogenesis</italic> published by Wiley Periodicals, Inc.</p> </sec> </abstract>