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The PRC1 Polycomb group complex interacts with PLZF/RARA to mediate leukemic transformation.

Genes & development | May 15, 2009

http://www.ncbi.nlm.nih.gov/pubmed/19451220

Ectopic repression of retinoic acid (RA) receptor target genes by PML/RARA and PLZF/RARA fusion proteins through aberrant recruitment of nuclear corepressor complexes drives cellular transformation and acute promyelocytic leukemia (APL) development. In the case of PML/RARA, this repression can be reversed through treatment with all-trans RA (ATRA), leading to leukemic remission. However, PLZF/RARA ectopic repression is insensitive to ATRA, resulting in persistence of the leukemic diseased state after treatment, a phenomenon that is still poorly understood. Here we show that, like PML/RARA, PLZF/RARA expression leads to recruitment of the Polycomb-repressive complex 2 (PRC2) Polycomb group (PcG) complex to RA response elements. However, unlike PML/RARA, PLZF/RARA directly interacts with the PcG protein Bmi-1 and forms a stable component of the PRC1 PcG complex, resulting in PLZF/RARA-dependent ectopic recruitment of PRC1 to RA response elements. Upon treatment with ATRA, ectopic recruitment of PRC2 by either PML/RARA or PLZF/RARA is lost, whereas PRC1 recruited by PLZF/RARA remains, resulting in persistent RA-insensitive gene repression. We further show that Bmi-1 is essential for the PLZF/RARA cellular transformation property and implicates a central role for PRC1 in PLZF/RARA-mediated myeloid leukemic development.

Pubmed ID: 19451220 RIS Download

Mesh terms: Antineoplastic Agents | Cell Transformation, Neoplastic | Chromatin | Humans | Leukemia | Nuclear Proteins | Oncogene Proteins, Fusion | Polycomb Repressive Complex 1 | Polycomb-Group Proteins | Protein Binding | Protein Structure, Tertiary | Proto-Oncogene Proteins | Repressor Proteins | Tretinoin | U937 Cells

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