Preclinical study demonstrates PHF19 activates PRC2 to drive tumorigenesis in multiple myeloma models, highlighting PRC2 inhibition as a viable therapeutic strategy.
Key Points
To determine the molecular mechanism by which the PRC2 cofactor PHF19 regulates chromatin modification, gene silencing, and tumorigenesis in multiple myeloma.
Analyzed PHF19 genomic amplification and expression profiles in multiple myeloma patient cohorts and cell line models.
Evaluated multiple myeloma tumor growth in vitro and in vivo following PHF19 genetic depletion alongside pharmacological PRC2 inhibitor testing.
Mapped epigenetic and gene expression alterations using chromatin immunoprecipitation sequencing (ChIP-seq) for H3K27me3 and transcriptomic RNA sequencing (RNA-seq).
PHF19 overexpression and genomic amplification correlate with malignant progression to plasma cell leukemia and worse clinical treatment outcomes.
Depletion of PHF19 disrupts broad H3K27me3 domain spreading from cytosine guanine dinucleotide islands and significantly suppresses multiple myeloma tumor growth in vitro and in vivo.
Loss of PHF19 restores the expression of silenced PRC2 target genes, including cell cycle inhibitors and interferon-JAK-STAT tumor suppressors, conferring sensitivity to PRC2 inhibitors.