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Background  The 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.    Methods  U937T_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.    Results  Gene 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.    Conclusions  Our 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 material  The online version of this article (doi:10.1186/s13045-015-0124-6) contains supplementary material, which is available to authorized users.

EVI1 promotes tumor growth via transcriptional repression of MS4A3