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

Yi Zhang1, Kristina Owens, Layla Hatem

  • 1Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY; and.

Blood
|September 12, 2013
PubMed

Insights

The MDS1-EVI1 (ME) protein, specifically its PR domain, is crucial for mixed-lineage leukemia (MLL) fusion protein-driven leukemia development. Targeting ME offers a potential new therapeutic strategy for this aggressive cancer.

Area of Science:

  • Hematology
  • Molecular Biology
  • Cancer Research

Background:

  • Mixed-lineage leukemia (MLL) fusion proteins (MFPs) are associated with poor prognosis.
  • The Mecom locus encodes MDS1-EVI1 (ME) proteins, including a PR domain-containing isoform crucial for histone methyltransferase activity.

Purpose of the Study:

  • To investigate the role of ME proteins in MLL-AF9-induced leukemogenesis.
  • To determine if the PR domain of ME is essential for MFP-induced transformation.

Main Methods:

  • Utilized ME-deficient mouse models for in vitro and in vivo transformation assays.
  • Assessed the transforming capacity of various fusion proteins in ME-deficient cells.
  • Investigated the necessity of the PR domain for MFP-induced transformation.

Main Results:

  • ME is essential for MLL-AF9-induced transformation in vitro and in vivo.
  • MLL-AF9 and MLL-ENL require ME for transformation, while other fusion proteins can transform ME-deficient cells.
  • The PR domain of ME is indispensable for MFP-induced leukemogenesis.

Conclusions:

  • MDS1-EVI1 (ME) protein, particularly its PR domain, plays a critical role in MLL fusion protein leukemia.
  • ME represents a potential novel therapeutic target for treating this subset of leukemias.

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