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. © 2014 The Authors. Molecular Carcinogenesis published by Wiley Periodicals, Inc.

CGRP Signaling via CALCRL Increases Chemotherapy Resistance and Stem Cell Properties in Acute Myeloid Leukemia

“…Concerning expression analyses, cells were prepared and, where indicated, treated with araC (4 µM for 48 h) as described previously [34,55]. Regarding metabolic activity assays, vitally frozen AML cells were thawed, washed with RPMI 1640 medium (Invitrogen, CA, USA) supplemented with 10% fetal bovine serum (FBS; Invitrogen), 1% Penicillin/Streptomycin/Glutamine (Invitrogen), and 5 µg/mL DNase (Sigma–Aldrich, Missouri, USA), and incubated for 60 min at 37 °C and 5% CO 2 with RPMI 1640 medium containing 10% FBS, 1% Penicillin/Streptomycin/Glutamine, and 50 µg/mL DNase to prevent cell clumping.…”

Id2 and E Proteins Orchestrate the Initiation and Maintenance of MLL-Rearranged Acute Myeloid Leukemia

“…A total of 261 DE genes were detected (140 up-and 121 downregulated; p < 0.01; log 2 FC % À0.6 or log 2 FC R 0.6; Table S4), and GSEA analysis showed that the gene-expression profile associated with ectopic expression of Id2 in Tet-off MLL-AF9 (MLL-AF9 ON) leukemias was highly enriched in genes negatively correlated with the LSC signature identified by Somervaille et al (2009) in MLL-rearranged leukemia ( Figure S5F). Id2 overexpression (Table S4) affected many genes involved in hematopoiesis, cytokine signaling, and inflammation/myeloid differentiation, including some previously reported to be associated with pro-(such as Gpr56, Cxxc5, and Prkca) or anti-leukemogenic (such as Tgif1 and Cadm1) effects in AML ( Figure S5G) (Fisser et al, 2015;Kornblau et al, 2006;Kuhnl et al, 2015;Pabst et al, 2016;Willer et al, 2015).…”

CADM1 promotes adhesion to vascular endothelial cells and transendothelial migration in cultured GIST cells

“…CADM1 expression is frequently lost in numerous types of epithelial neoplasms ( 13 – 15 ), and CADM1 is considered to be a tumor suppressor in epithelial neoplasms. In contrast, upregulated CADM1 appears to promote ATLL ( 16 ) and AML ( 17 ) progression through enhancement of tumor cell growth, tissue invasion, and adhesion to the vascular endothelium ( 18 ). There is also recent research that high CADM1 expression in SCLCs might promote the malignant features of the cancer ( 19 , 20 ).…”

“…Therefore, CADM1 in those cancers is considered to act as a tumor suppressor. In contrast, CADM1 appears to be a tumor promoter in adult T cell leukemia/lymphoma (ATLL) ( 16 ) and acute myelocytic leukemia ( 17 , 18 ), which show high CADM1 expression with enhancement of tumor growth, tissue invasion by the tumor cells, and tumor cell adhesion to the vascular endothelium ( 18 ). Recent research also reported that CADM1 is highly expressed in ~80% of small cell lung cancers (SCLCs) and promotes malignant features of them ( 19 , 20 ).…”