The Zinc Finger Transcription Factor Mds1‐Evi1 Forms a Novel Protein Complex in MLL leukemia

Abstract

The dual transcription factor‐methyltransferase Mds1‐Evi1 is frequently overexpressed in high‐risk leukemias. Mds1‐Evi1 contributes to leukemias induced by the mixed lineage leukemia (MLL) fusion protein MLL‐AF9, although the mechanism is unknown. MLL contains chromatin‐targeting and histone lysine methyltransferase domains, and fusion to AF9 can cause aberrant protein recruitment to target genes. Although Mds1‐Evi1 contains a methyltransferase domain, it does not appear to act on histones. Therefore, we are interested in how protein‐protein interactions involving Mds1‐Evi1 contribute to leukemogenesis. Many known interactors of MLL and Mds1‐Evi1 include chromatin modifying enzymes, suggesting that coordination between epigenetic modulators is key in leukemia pathogenesis.Here, we report the biochemical purification of a novel Mds1‐Evi1‐containing protein complex using a unique murine model of leukemia. To isolate the complex, we induced acute MLL‐AF9 leukemia in mice containing a tandem affinity purification (TAP) tag knocked into the endogenous Mds1‐Evi1 gene. Leukemic spleen tissue from these mice was used to purify the TAP‐tagged protein complex. Proteomic analysis revealed several members of the SWI/SNF chromatin remodeling complex, which is involved in epigenetic control of a variety of gene programs. Association between Mds1‐Evi1 and SWI/SNF may allow the activation of cell‐cycle and differentiation programs, contributing to transformation. SWI/SNF also coordinates with MLL fusion proteins to activate the Hox family of leukemia oncogenes. Our results provide a link between Mds1‐Evi1 and the chromatin remodeling machinery, where abnormal coordination of Mds1‐Evi1, MLL‐AF9 and SWI/SNF may lead to gene activation and the development of leukemia.