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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
NUP98 fusion proteins and KMT2A-MENIN antagonize PRC1.1 to drive gene expression in AML
Emily B Heikamp1, Cynthia Martucci1, Jill A Henrich2
1Department of Pediatric Oncology, Dana-Farber Cancer Institute, and Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA 02215, USA.
Abstract:
Control of stem cell-associated genes by Trithorax group (TrxG) and Polycomb group (PcG) proteins is frequently misregulated in cancer. In leukemia, oncogenic fusion proteins hijack the TrxG homolog KMT2A and disrupt PcG activity to maintain pro-leukemogenic gene expression, though the mechanisms by which oncofusion proteins antagonize PcG proteins remain unclear. Here, we define the relationship between NUP98 oncofusion proteins and the non-canonical polycomb repressive complex 1.1 (PRC1.1) in leukemia using Menin-KMT2A inhibitors and targeted degradation of NUP98 fusion proteins. Eviction of the NUP98 fusion-Menin-KMT2A complex from chromatin is not sufficient to silence pro-leukemogenic genes. In the absence of PRC1.1, key oncogenes remain transcriptionally active. Transition to a repressed chromatin state requires the accumulation of PRC1.1 and repressive histone modifications. We show that PRC1.1 loss leads to resistance to small-molecule Menin-KMT2A inhibitors in vivo. Therefore, a critical function of oncofusion proteins that hijack Menin-KMT2A activity is antagonizing repressive chromatin complexes.
Insights
Oncogenic fusion proteins in leukemia disrupt gene silencing by antagonizing Polycomb Repressive Complex 1.1 (PRC1.1), a key mechanism for maintaining cancer-promoting genes and drug resistance.
Area of Science:
- Epigenetics
- Cancer Biology
- Molecular Oncology
Background:
- Trithorax group (TrxG) and Polycomb group (PcG) proteins regulate stem cell genes, with their misregulation implicated in cancer.
- In leukemia, oncogenic fusion proteins like NUP98 hijack KMT2A and impair PcG function to sustain pro-leukemogenic gene expression.
Purpose of the Study:
- To investigate the interaction between NUP98 oncofusion proteins and the non-canonical Polycomb Repressive Complex 1.1 (PRC1.1) in leukemia.
- To elucidate the mechanisms by which oncofusion proteins antagonize PcG proteins and maintain leukemic gene expression.
Main Methods:
- Utilized Menin-KMT2A inhibitors to study the role of KMT2A fusion proteins.
- Employed targeted degradation of NUP98 fusion proteins to assess their impact on chromatin state.
- Analyzed the requirement of PRC1.1 for gene silencing and drug sensitivity in leukemia models.
Main Results:
- Removing NUP98-Menin-KMT2A complexes from chromatin alone does not silence oncogenes.
- The Polycomb Repressive Complex 1.1 (PRC1.1) is essential for establishing a repressed chromatin state and silencing key oncogenes.
- Loss of PRC1.1 confers resistance to Menin-KMT2A inhibitors in vivo, highlighting its role in drug sensitivity.
Conclusions:
- Oncofusion proteins that target Menin-KMT2A activity critically antagonize repressive chromatin complexes like PRC1.1.
- PRC1.1 accumulation and repressive histone marks are required for effective oncogene silencing.
- Targeting the interaction between oncofusion proteins and PRC1.1 may offer novel therapeutic strategies for leukemia.
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