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PHF19 promotes multiple myeloma tumorigenicity through PRC2 activation

Zhihong Ren, Jeong Hyun Ahn, Hequn Liu, Yi-Hsuan Tsai, Natarajan V. Bhanu, Brian Koss, David F. Allison, Anqi Ma, Aaron J. Storey, Ping Wang, Samuel G. Mackintosh, Ricky D. Edmondson, Richard W.J. Groen, Anton C. Martens, Benjamin A. Garcia, Alan J. Tackett, Jian Jin, Ling Cai, Deyou Zheng and Gang Greg Wang

Key Points

  • PHF19 is required for multiple myeloma (MM) growth in vitro and in vivo, correlating positively with poorer outcomes in the clinic.

  • PHF19 potentiates MM tumorigenicity via the associated PRC2, which renders a sensitivity of MM cells to PRC2 inhibitors.

Abstract

Dysregulation of Polycomb Repressive Complex 2 (PRC2) promotes development of hematological malignancies partly through catalyzing trimethylation of histone H3 lysine 27 (H3K27me3). However, it remains to be fully determined how PRC2 activity is mis-regulated in various blood cancer types. We here report a PRC2-associated factor, PHD finger protein 19 (PHF19), as a crucial mediator of oncogenesis in multiple myeloma (MM). Overexpression and/or genomic amplification of PHF19 is found associated with malignant progression of MM and plasma cell leukemia patients, correlating to their poorer prognosis in the clinic. Using various MM models, we demonstrated a critical requirement of PHF19 for tumor growth in vitro and in vivo. Mechanistically, PHF19-mediated oncogenic effect relies on its physical interaction to PRC2, as well as PHF19's chromatin-binding functions. ChIP-Seq and RNA-Seq profilings showed an essential role of PHF19 in the maintenance of H3K27me3 patterns and optimal repression of PRC2 targets in MM cells, which include the cell cycle inhibitor and JAK-STAT signaling genes crucial for MM oncogenesis. Correlation studies using transcriptome datasets of MM patient samples further support a clinical relevance of the PHF19-regulated pathways. Lastly, we show that MM cells are generally sensitive to PRC2 inhibitors. Collectively, this study demonstrates that PHF19 promotes MM tumorigenesis through enhancing PRC2's gene-regulatory functions, lending support for PRC2 blockade as a means for MM therapeutics.

  • Submitted March 12, 2019.
  • Revision received August 1, 2019.
  • Accepted July 24, 2019.