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PHF19 inhibition as a therapeutic target in multiple myeloma
Carolina D Schinke1, Jordan T Bird2, Pingping Qu3
1Myeloma Center, Division of Hematology/Oncology, Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AR, United States.
Abstract:
Epigenetic deregulation is increasingly recognized as a contributing pathological factor in multiple myeloma (MM). In particular tri-methylation of H3 lysine 27 (H3K27me3), which is catalyzed by PHD finger protein 19 (PHF19), a subunit of the Polycomb Repressive Complex 2 (PRC2), has recently shown to be a crucial mediator of MM tumorigenicity. Overexpression of PHF19 in MM has been associated with worse clinical outcome. Yet, while there is mounting evidence that PHF19 overexpression plays a crucial role in MM carcinogenesis downstream mechanisms remain to be elucidated. In the current study we use a functional knock down (KD) of PHF19 to investigate the biological role of PHF19 and show that PHF19KD leads to decreased tumor growth in vitro and in vivo. Expression of major cancer players such as bcl2, myc and EGR1 were decreased upon PHF19KD further underscoring the role of PHF19 in MM biology. Additionally, our results highlighted the prognostic impact of PHF19 overexpression, which was significantly associated with worse survival. Overall, our study underscores the premise that targeting the PHF19-PRC2 complex would open up avenues for novel MM therapies.
Insights
PHD finger protein 19 (PHF19) drives multiple myeloma (MM) growth by regulating cancer genes. Reducing PHF19 inhibits tumor progression and improves survival, suggesting PHF19-PRC2 is a therapeutic target.
Area of Science:
- Epigenetics
- Molecular Biology
- Oncology
Background:
- Epigenetic deregulation contributes to multiple myeloma (MM) pathogenesis.
- PHD finger protein 19 (PHF19), a Polycomb Repressive Complex 2 (PRC2) subunit, catalyzes H3K27me3 and is overexpressed in MM, correlating with poor outcomes.
- The precise mechanisms by which PHF19 drives MM tumorigenicity require further investigation.
Purpose of the Study:
- To investigate the biological role of PHF19 in multiple myeloma.
- To elucidate the downstream mechanisms of PHF19 in MM carcinogenesis.
- To assess the therapeutic potential of targeting the PHF19-PRC2 complex in MM.
Main Methods:
- Functional knockdown (KD) of PHF19 in MM cells.
- In vitro and in vivo tumor growth assays.
- Analysis of key cancer gene expression (bcl2, myc, EGR1) following PHF19 KD.
Main Results:
- PHF19 knockdown significantly decreased MM tumor growth both in vitro and in vivo.
- PHF19 KD led to reduced expression of critical oncogenes including bcl2, myc, and EGR1.
- PHF19 overexpression was confirmed as a significant prognostic marker for worse survival in MM patients.
Conclusions:
- PHF19 plays a critical role in MM biology and tumorigenesis.
- Targeting the PHF19-PRC2 complex presents a promising therapeutic strategy for multiple myeloma.
- PHF19 is a potential therapeutic target for novel MM treatments.
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