Multiple mechanisms deregulate EZH2 and histone H3 lysine 27 epigenetic changes in myeloid malignancies

Area of Science:

• Epigenetics and Transcriptional Regulation
• Cancer Genomics
• Hematologic Malignancies

Background:

• Polycomb repressive complex 2 (PRC2) epigenetically silences genes through histone H3 lysine 27 trimethylation (H3K27me3).
• Enhancer of zeste homolog 2 (EZH2) is the catalytic subunit of PRC2, crucial for its function.
• EZH2 mutations in myeloid malignancies are typically inactivating, unlike in B-cell lymphomas.

Purpose of the Study:

• To investigate the frequency and functional impact of EZH2 and associated PRC2 component mutations in myeloid malignancies.
• To explore the relationship between reduced EZH2 expression/activity and gene dysregulation in leukemogenesis.
• To identify downstream targets affected by EZH2 loss-of-function in these cancers.

Main Methods:

• Analysis of mutational status in a cohort of 469 myeloid malignancy cases.
• Assessment of EZH2 expression levels in relation to genetic alterations (mutations, deletions) and spliceosomal mutations.
• Evaluation of H3K27me3 levels, chromatin accessibility, and gene expression, particularly for HOX genes.

Main Results:

• EZH2 mutations were found in 8% of cases; EED/SUZ12 mutations in 3.3%.
• Reduced EZH2 expression correlated with hemizygous deletion (-7/del7q) and spliceosomal mutations (U2AF1/SRSF2).
• EZH2 loss-of-function led to decreased H3K27me3, increased chromatin relaxation, and overexpression of HOXA9, a key stem cell regulator.

Conclusions:

• Inactivating mutations and reduced expression of EZH2 are common in myeloid malignancies.
• Loss of PRC2-mediated gene repression, indicated by reduced H3K27me3, contributes to leukemogenesis.
• Dysregulation of HOX genes is a significant downstream consequence of impaired EZH2 function in these cancers.