Browsing by Author "Auclair, Daniel"

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    Insights into high-risk multiple myeloma from an analysis of the role of PHF19 in cancer
    (Springer Nature, 2021-12-02) Ghamlouch, Hussein; Boyle, Eileen M.; Blaney, Patrick; Wang, Yubao; Choi, Jinyoung; Williams, Louis; Bauer, Michael; Auclair, Daniel; Bruno, Benedetto; Walker, Brian A.; Davies, Faith E.; Morgan, Gareth J.; Medicine, School of Medicine
    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.
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    Perspectives on the Risk-Stratified Treatment of Multiple Myeloma
    (American Association for Cancer Research, 2022) Davies, Faith E.; Pawlyn, Charlotte; Usmani, Saad Z.; San-Miguel, Jesus F.; Einsele, Hermann; Boyle, Eileen M.; Corre, Jill; Auclair, Daniel; Cho, Hearn Jay; Lonial, Sagar; Sonneveld, Pieter; Stewart, A. Keith; Bergsagel, P. Leif; Kaiser, Martin F.; Weisel, Katja; Keats, Jonathan J.; Mikhael, Joseph R.; Morgan, Kathryn E.; Ghobrial, Irene M.; Orlowski, Robert Z.; Landgren, C. Ola; Gay, Francesca; Caers, Joseph; Chng, Wee Joo; Chari, Ajai; Walker, Brian A.; Kumar, Shaji K.; Costa, Luciano J.; Anderson, Kenneth C.; Morgan, Gareth J.; Medicine, School of Medicine
    The multiple myeloma treatment landscape has changed dramatically. This change, paralleled by an increase in scientific knowledge, has resulted in significant improvement in survival. However, heterogeneity remains in clinical outcomes, with a proportion of patients not benefiting from current approaches and continuing to have a poor prognosis. A significant proportion of the variability in outcome can be predicted on the basis of clinical and biochemical parameters and tumor-acquired genetic variants, allowing for risk stratification and a more personalized approach to therapy. This article discusses the principles that can enable the rational and effective development of therapeutic approaches for high-risk multiple myeloma.