The Polycomb complex PRC2 supports aberrant self-renewal in a mouse model of MLL-AF9;Nras(G12D) acute myeloid leukemia.

Abstract

The Trithorax and Polycomb groups of chromatin regulators are critical for cell-lineage specification during normal development; functions that often become deregulated during tumorigenesis. As an example, oncogenic fusions of the Trithorax-related protein mixed lineage leukemia (MLL) can initiate aggressive leukemias by altering the transcriptional circuitry governing hematopoietic cell differentiation, a process that requires multiple epigenetic pathways to implement. Here we used shRNA screening to identify chromatin regulators uniquely required in a mouse model of MLL-fusion acute myeloid leukemia, which revealed a role for the Polycomb repressive complex 2 (PRC2) in maintenance of this disease. shRNA-mediated suppression of PRC2 subunits Eed, Suz12 or Ezh1/Ezh2 led to proliferation arrest and differentiation of leukemia cells, with a minimal impact on growth of several non-transformed hematopoietic cell lines. The requirement for PRC2 in leukemia is partly because of its role in direct transcriptional repression of genes that limit the self-renewal potential of hematopoietic cells, including Cdkn2a. In addition to implicating a role for PRC2 in the pathogenesis of MLL-fusion leukemia, our results suggest, more generally, that Trithorax and Polycomb group proteins can cooperate with one another to maintain aberrant lineage programs in cancer.

• Authors: J Shi, E Wang, J Zuber, A Rappaport, M Taylor, C Johns, S W Lowe, C R Vakoc
• Journal: Oncogene (Oncogene) Vol. 32 Issue 7 Pg. 930-8 (Feb 14 2013) ISSN: 1476-5594 [Electronic] England
• PMID: 22469984 (Publication Type: Journal Article, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)

Chemical References

• MLL-AF9 fusion protein, mouse
• Oncogene Proteins, Fusion
• Polycomb-Group Proteins
• Suz12 protein, mouse
• Aspartic Acid
• Polycomb Repressive Complex 2
• Glycine

Topics

• Amino Acid Substitution
• Animals
• Aspartic Acid (genetics)
• Cell Proliferation
• Disease Models, Animal
• Genes, ras (genetics)
• Glycine (genetics)
• Humans
• Leukemia, Myeloid, Acute (genetics, metabolism, pathology)
• Mice
• Mice, Transgenic
• Models, Biological
• Mutation, Missense (physiology)
• Oncogene Proteins, Fusion (genetics)
• Polycomb Repressive Complex 2 (genetics, metabolism, physiology)
• Polycomb-Group Proteins (genetics, physiology)
• Tumor Cells, Cultured