Mi-2/NuRD (Nucleosome Remodeling and Deacetylase) chromatin remodeling complex (CRC), an assemblage of proteins that combine key epigenetic regulators necessary for histone deacetylation and demethylation, is known to be an epigenetic reader of DNA methylation that regulates genes involved in normal development and neoplastic diseases. To our surprise, we have found that MBD2 and MBD3 are downregulated, with no disruption of the integrity of the Mi-2/NuRD complex, during terminal differentiation of MEL cells in vitro as well as normal erythropoiesis in the bone marrow. In further, we confirmed that MBD2 downregulation potentiates terminal erythroid differentiation and transcriptional activation of both α- and β-globin genes via recruitment of TFCP2 (CP2c) TF complexes to their promoters. In accordance with the previous report that MBD2 recruits the CHD4 nucleosome remodeling protein to the complex via a coiled-coil interaction with GATAD2A (p66α), spontaneous differentiation of MEL cells occurred by arbitral disruption of MBD2-p66α interaction or MBD2 knock down. Along with previous report that MBD2 knock out mice are viable and fertile, our data indicate that MBD2-p66α interaction is involves in gene silencing in general, but is dispensable in normal differentiation of some types of cells, i.e., erythroid lineage cells and also strongly suggest that disruption of MBD2-p66α interaction induces normal differentiation or cell death of some types of leukemia, like MEL cells which are arrested at the proerythroid stage. Based on this, we identified small molecules disrupting MBD2-p66α interaction using a computer aided molecular docking and tested their usefulness as an anticancer drug in various available cancer cell lines. We found that a drug 086567 shows a specific anticancer effect to myeloid leukemia cells with IC50 = ~20 μM, and also confirmed its anticancer effect in the mouse xenograft model of MEL cells. Mechanistically, this drug causes cell cycle arrest at various stages, leading to chromosomal aneuploidy and apoptotic gene expression.