Blood Journal
Leading the way in experimental and clinical research in hematology

Essential role of PR-domain protein MDS1-EVI1 in MLL-AF9 leukemia

  1. Yi Zhang1,
  2. Kristina Owens1,
  3. Layla Hatem1,
  4. Carolyn H. Glass1,
  5. Kannan Karuppaiah1,
  6. Fernando Camargo2, and
  7. Archibald S. Perkins1,*
  1. 1 Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, United States;
  2. 2 Stem Cell Program, Children's Hospital, Harvard Medical School, Boston, MA, United States
  1. * Corresponding author; email: archibald_perkins{at}

Key points

  • The MDS1-EVI1 isoform of the MECOM locus is required for MLL-AF9-induced myleoid leukemia

  • Within MDS1-EVI1, it is the PR domain that is essential


A subgroup of leukemogenic MLL fusion proteins (MFP) including MLL-AF9 activates Mecom locus, and exhibits extremely poor clinical prognosis. Mecom encodes EVI1 and MDS1-EVI1 (ME) proteins via alternative transcription start sites; these differ by the presence of a histone methyltransferase domain in the ME isoform. Using an ME-deficient mouse, we show that ME is required for MLL-AF9-induced transformation both in vitro and in vivo. And, while Nup98-HOXA9, MEIS1-HOXA9, and E2A-Hlf could transform ME-deficient cells, both MLL-AF9 and MLL-ENL were ineffective, indicating the ME requirement is specific to MLL fusion leukemia. Further, we show the PR domain is essential for MFP-induced transformation. These studies clearly indicate an essential role of PR-domain protein ME in MFP leukemia, suggesting that ME may be a novel target for therapeutic intervention for this group of leukemias.

  • Submitted August 31, 2012.
  • Accepted August 5, 2013.