Blocking a Protein Complex Cures Acute Myeloid Leukemia in a Mouse Model

Cancer researchers have found that the activity of a specific protein complex was required to maintain the abnormal expression of DNA that characterizes the blood cell cancer, acute myeloid leukemia (AML).

The protein complex, PRC2 (Polycomb Repressive Complex 2), is one of the two classes of Polycomb-group proteins or (PcG). This complex has histone methyltransferase activity and primarily trimethylates histone H3 on lysine 27, a mark of transcriptionally silent chromatin. PRC2 is required for initial targeting of genomic region (PRC Response Elements or PRE) to be silenced, while PRC1 is required for stabilizing this silencing and underlies cellular memory of the silenced region after cellular differentiation. These proteins are required for long term epigenetic silencing of chromatin and have an important role in stem cell differentiation and early embryonic development. PRC2 are present in all multicellular organisms. Additionally, PRC2 have a role in X chromosome inactivation, in maintenance of stem cell fate, and in imprinting. Aberrant expression of PRC2 has been observed in some types of cancer.

Investigators at Cold Spring Harbor Laboratory (NY, USA) used shRNA (short hairpin RNA) screening to identify chromatin regulators uniquely required in a mouse model of mixed lineage leukemia (MLL)-fusion AML.

They reported in the April 2, 2012, online edition of the journal Oncogene that 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 nontransformed blood-forming cell lines. Blocking PRC2 induced the reactivation of a powerful anti-tumor pathway that protected a mouse model against AML.

"Our results emphasize the idea that targeting chromatin regulators is an effective means of reawakening growth-halting mechanisms that lie dormant in most cancer cells," said senior author Dr. Chris Vakoc, an assistant professor at Cold Spring Harbor Laboratory. "A growing body of evidence suggests that AML can arise from dysregulation of the epigenetic machinery that controls chromatin."

"Epigenetic regulators such as PRC2 are considered druggable and therefore are good surrogate targets," said Dr. Vakoc. "Targeting Brd4, for example, is a great way to switch off the Myc oncogene. And as this study shows, targeting PRC2 is a great way of switching on the Ink4/Arf tumor suppressors."

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Cold Spring Harbor Laboratory