EVI1 is critical for the pathogenesis of a subset of MLL-AF9-rearranged AMLs

Blood. 2012 Jun 14;119(24):5838-49. doi: 10.1182/blood-2011-11-393827. Epub 2012 May 2.

Abstract

The proto-oncogene EVI1 (ecotropic viral integration site-1), located on chromosome band 3q26, is aberrantly expressed in human acute myeloid leukemia (AML) with 3q26 rearrangements. In the current study, we showed, in a large AML cohort carrying 11q23 translocations, that ∼ 43% of all mixed lineage leukemia (MLL)-rearranged leukemias are EVI1(pos). High EVI1 expression occurs in AMLs expressing the MLL-AF6, -AF9, -AF10, -ENL, or -ELL fusion genes. In addition, we present evidence that EVI1(pos) MLL-rearranged AMLs differ molecularly, morphologically, and immunophenotypically from EVI1(neg) MLL-rearranged leukemias. In mouse bone marrow cells transduced with MLL-AF9, we show that MLL-AF9 fusion protein maintains Evi1 expression on transformation of Evi1(pos) HSCs. MLL-AF9 does not activate Evi1 expression in MLL-AF9-transformed granulocyte macrophage progenitors (GMPs) that were initially Evi1(neg). Moreover, shRNA-mediated knockdown of Evi1 in an Evi1(pos) MLL-AF9 mouse model inhibits leukemia growth both in vitro and in vivo, suggesting that Evi1 provides a growth-promoting signal. Using the Evi1(pos) MLL-AF9 mouse leukemia model, we demonstrate increased sensitivity to chemotherapeutic agents on reduction of Evi1 expression. We conclude that EVI1 is a critical player in tumor growth in a subset of MLL-rearranged AMLs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Marrow Cells / metabolism
  • Bone Marrow Cells / pathology
  • Cell Proliferation
  • Cell Transformation, Neoplastic / genetics
  • Chromosomes, Human, Pair 11 / genetics
  • Colony-Forming Units Assay
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Gene Expression Profiling
  • Gene Expression Regulation, Leukemic
  • Gene Knockdown Techniques
  • Gene Rearrangement / genetics*
  • Histones / metabolism
  • Humans
  • Leukemia, Myeloid, Acute / classification*
  • Leukemia, Myeloid, Acute / etiology
  • Leukemia, Myeloid, Acute / genetics*
  • Lysine / metabolism
  • MDS1 and EVI1 Complex Locus Protein
  • Mice
  • Mice, Inbred C57BL
  • Myeloid-Lymphoid Leukemia Protein / genetics*
  • Oncogene Proteins, Fusion / genetics*
  • Promoter Regions, Genetic / genetics
  • Proto-Oncogene Mas
  • Proto-Oncogenes / genetics
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*

Substances

  • DNA-Binding Proteins
  • Histones
  • MAS1 protein, human
  • MDS1 and EVI1 Complex Locus Protein
  • MECOM protein, human
  • MLL-AF9 fusion protein, human
  • Mecom protein, mouse
  • Oncogene Proteins, Fusion
  • Proto-Oncogene Mas
  • RNA, Messenger
  • Transcription Factors
  • Myeloid-Lymphoid Leukemia Protein
  • Lysine