Myeloma Research Program, NYU Langone Medical Center, Perlmutter Cancer Center, 522 1st Avenue, Manhattan, New York City, NY, 10016, USA.
Applied Bioinformatics Laboratories (ABL), NYU Langone Medical Center, New York, NY, USA.
J Exp Clin Cancer Res. 2021 Dec 2;40(1):380. doi: 10.1186/s13046-021-02185-1.
Despite improvements in outcome, 15-25% of newly diagnosed multiple myeloma (MM) patients have treatment resistant high-risk (HR) disease with a poor survival. The lack of a genetic basis for HR has focused attention on the role played by epigenetic changes. Aberrant expression and somatic mutations affecting genes involved in the regulation of tri-methylation of the lysine (K) 27 on histone 3 H3 (H3K27me3) are common in cancer. H3K27me3 is catalyzed by EZH2, the catalytic subunit of the Polycomb Repressive Complex 2 (PRC2). The deregulation of H3K27me3 has been shown to be involved in oncogenic transformation and tumor progression in a variety of hematological malignancies including MM. Recently we have shown that aberrant overexpression of the PRC2 subunit PHD Finger Protein 19 (PHF19) is the most significant overall contributor to HR status further focusing attention on the role played by epigenetic change in MM. By modulating both the PRC2/EZH2 catalytic activity and recruitment, PHF19 regulates the expression of key genes involved in cell growth and differentiation. Here we review the expression, regulation and function of PHF19 both in normal and the pathological contexts of solid cancers and MM. We present evidence that strongly implicates PHF19 in the regulation of genes important in cell cycle and the genetic stability of MM cells making it highly relevant to HR MM behavior. A detailed understanding of the normal and pathological functions of PHF19 will allow us to design therapeutic strategies able to target aggressive subsets of MM.
尽管在治疗结果方面取得了进展，但仍有 15-25%的新诊断多发性骨髓瘤（MM）患者患有治疗抵抗的高危（HR）疾病，其生存率较差。由于 HR 缺乏遗传基础，人们开始关注表观遗传变化的作用。异常表达和体细胞突变影响参与组蛋白 3 H3（H3）赖氨酸（K）27 三甲基化（H3K27me3）调节的基因，这在癌症中很常见。H3K27me3 由多梳抑制复合物 2（PRC2）的催化亚基 EZH2 催化。H3K27me3 的失调已被证明与多种血液恶性肿瘤（包括 MM）中的致癌转化和肿瘤进展有关。最近，我们发现 PRC2 亚基 PHD 指蛋白 19（PHF19）的异常过表达是导致 HR 状态的最重要因素，这进一步关注了表观遗传变化在 MM 中的作用。PHF19 通过调节 PRC2/EZH2 的催化活性和募集，调节参与细胞生长和分化的关键基因的表达。在这里，我们综述了 PHF19 在实体瘤和 MM 的正常和病理环境中的表达、调节和功能。我们提供的证据强烈表明 PHF19 参与了对 MM 细胞中细胞周期和遗传稳定性重要的基因的调节，使其与 HR MM 的行为高度相关。对 PHF19 的正常和病理功能的详细了解将使我们能够设计能够靶向 MM 侵袭性亚群的治疗策略。
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