EVI1 promotes tumor growth via transcriptional repression of MS4A3

Abstract

BackgroundThe transcription factor Ecotropic Virus Integration site 1 (EVI1) regulates cellular proliferation, differentiation, and apoptosis, and its overexpression contributes to an aggressive course of disease in myeloid leukemias and other malignancies. Notwithstanding, knowledge about the target genes mediating its biological and pathological functions remains limited. We therefore aimed to identify and characterize novel EVI1 target genes in human myeloid cells.MethodsU937T_EVI1, a human myeloid cell line expressing EVI1 in a tetracycline regulable manner, was subjected to gene expression profiling. qRT-PCR was used to confirm the regulation of membrane-spanning-4-domains subfamily-A member-3 (MS4A3) by EVI1. Reporter constructs containing various parts of the MS4A3 upstream region were employed in luciferase assays, and binding of EVI1 to the MS4A3 promoter was investigated by chromatin immunoprecipitation. U937 derivative cell lines experimentally expressing EVI1 and/or MS4A3 were generated by retroviral transduction, and tested for their tumorigenicity by subcutaneous injection into severe combined immunodeficient mice.ResultsGene expression microarray analysis identified 27 unique genes that were up-regulated, and 29 unique genes that were down-regulated, in response to EVI1 induction in the human myeloid cell line U937T. The most strongly repressed gene was MS4A3, and its down-regulation by EVI1 was confirmed by qRT-PCR in additional, independent experimental model systems. MS4A3 mRNA levels were also negatively correlated with those of EVI1 in several published AML data sets. Reporter gene assays and chromatin immunoprecipitation showed that EVI1 regulated MS4A3 via direct binding to a promoter proximal region. Experimental re-expression of MS4A3 in an EVI1 overexpressing cell line counteracted the tumor promoting effect of EVI1 in a murine xenograft model by increasing the rate of apoptosis.ConclusionsOur data reveal MS4A3 as a novel direct target of EVI1 in human myeloid cells, and show that its repression plays a role in EVI1 mediated tumor aggressiveness.Electronic supplementary materialThe online version of this article (doi:10.1186/s13045-015-0124-6) contains supplementary material, which is available to authorized users.

EVI1 as a Marker for Lymph Node Metastasis in HNSCC

“…Ecotropic Viral Integration Site 1 (EVI1) was originally described in murine tumors as a retroviral integration site [1]. It is expressed in hematopoietic stem cells [2] and very well studied in myeloid leukemias as a marker for an aggressive disease with poor survival [3][4][5][6][7]. Moreover, in several solid tumors, an EVI1 overexpression indicates poor survival.…”

“…But EVI1 is not just a prognostic marker. The relevance of EVI1 for cancer biology was demonstrated by showing that EVI1 targets some genes involved in carcinogenesis [7,15]. In sequencing analyses, HPV related uterine cervical cancer showed amplification changes for EVI1 in the 3q26 region as well [16].…”

TMEM140 is associated with the prognosis of glioma by promoting cell viability and invasion

“…Unstrained cell proliferation is one of the most remarkable features of malignancies. Abnormal regulation in cell cycle and cell apoptosis frequently results in aberrant cell proliferation in cancer [ 26 – 29 ]. Here, the silencing of TMEM140 by siRNA transfection significantly induced G1-phase arrest (Fig.…”

Ecotropic viral integration site 1 regulates the progression of acute myeloid leukemia via MS4A3‑mediated TGFβ/EMT signaling pathway

“…MS4A3 is a member of a family of four-transmembrane proteins, which acts as a cell surface signaling molecule and an intracellular adapter protein (27). Heller et al (12) indicated that Evi1 may promote tumor growth via transcriptional repression of MS4A3. The results of the present study confirmed previous results and reported that Evi1 regulated MS4A3 via regulation of miR-431 levels.…”

“…Jazaeri et al (11) reported that Evi1 and EVI1s (Delta324) may be regarded as potential therapeutic targets in ovarian cancer. In addition, the transcription factor Evi1 may regulate cellular proliferation, differentiation and apoptosis, and its overexpression may contribute to an aggressive course of disease via transcriptional repression of membrane-spanning-4-domains subfamily-A member-3 (MS4A3) in AML and other malignancies (12). Furthermore, the results indicated that Evi1 is a transcriptional suppressor of the microRNA (miRNA)-143 gene, and miRNA-143 mediates its action via the K-Ras axis in human colon cancer (13).…”