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Investigation of the Transcriptional Role of a RUNX1 Intronic Silencer by CRISPR/Cas9 Ribonucleoprotein in Acute Myeloid Leukemia Cells
Published on: September 1, 2019
The PRC1 Polycomb group complex interacts with PLZF/RARA to mediate leukemic transformation
Hanane Boukarabila1, Andrew J Saurin, Eric Batsché
1Centre d'Immunologie de Marseille-Luminy (CIML), Université de la Méditerranée, Campus de Luminy, 13288 Marseille Cedex 09, France.
Genes & Development
|May 20, 2009
Summary
Fusion proteins PML/RARA and PLZF/RARA drive acute promyelocytic leukemia (APL). Unlike PML/RARA, PLZF/RARA repression persists after all-trans retinoic acid (ATRA) treatment due to sustained Polycomb repressive complex 1 (PRC1) recruitment.
Area of Science:
- Molecular Biology
- Cancer Biology
- Epigenetics
Background:
- Acute promyelocytic leukemia (APL) involves oncogenic fusion proteins PML/RARA and PLZF/RARA.
- These proteins aberrantly recruit corepressors, repressing retinoic acid (RA) target genes and driving leukemogenesis.
- While PML/RARA-mediated repression is reversible with all-trans RA (ATRA), PLZF/RARA-mediated repression is ATRA-insensitive, a key difference in disease persistence.
Purpose of the Study:
- To elucidate the molecular mechanisms underlying ATRA-insensitive repression by PLZF/RARA.
- To investigate the differential recruitment of Polycomb group (PcG) complexes by PML/RARA and PLZF/RARA.
- To determine the role of Bmi-1 and PRC1 in PLZF/RARA-driven leukemogenesis.
Main Methods:
- Chromatin immunoprecipitation assays to assess PcG complex recruitment.
- Co-immunoprecipitation to analyze protein-protein interactions.
- Assessment of cellular transformation and leukemic development in relevant models.
Main Results:
- Both PML/RARA and PLZF/RARA recruit Polycomb-repressive complex 2 (PRC2) to RA response elements.
- PLZF/RARA, but not PML/RARA, directly interacts with Bmi-1 and stably incorporates into the PRC1 complex.
- PLZF/RARA mediates ectopic recruitment of PRC1 to RA response elements, which persists after ATRA treatment, unlike PRC2.
- Bmi-1 is essential for PLZF/RARA's cellular transformation activity.
Conclusions:
- PLZF/RARA-mediated ATRA resistance is due to sustained recruitment of PRC1, mediated by Bmi-1.
- PRC1 plays a critical role in PLZF/RARA-driven myeloid leukemic development.
- Targeting PRC1 may offer therapeutic strategies for ATRA-resistant APL.
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