Multiple Myeloma DREAM Challenge reveals epigenetic regulator PHF19 as marker of aggressive disease

Abstract

While the past decade has seen meaningful improvements in clinical outcomes for multiple myeloma patients, a subset of patients does not benefit from current therapeutics for unclear reasons. Many gene expression-based models of risk have been developed, but each model uses a different combination of genes and often involves assaying many genes making them difficult to implement. We organized the Multiple Myeloma DREAM Challenge, a crowdsourced effort to develop models of rapid progression in newly diagnosed myeloma patients and to benchmark these against previously published models. This effort lead to more robust predictors and found that incorporating specific demographic and clinical features improved gene expression-based models of high risk. Furthermore, post-challenge analysis identified a novel expression-based risk marker, PHF19, which has recently been found to have an important biological role in multiple myeloma. Lastly, we show that a simple four feature predictor composed of age, ISS, and expression of PHF19 and MMSET performs similarly to more complex models with many more gene expression features included.

Epigenetic Aberrations in Multiple Myeloma

“…Therefore, PHF19 role in modulating MM biology has been a matter of investigation. Expression of PHF19 was reported as significantly associated with MM disease progression, showing a predictive value greater than NSD2 [ 47 ], an oncogene frequently over-expressed in MM plasma cells harboring the high-risk t(4;14) translocation; and reported to modulate by the oncogene NSD2 [ 48 ]. These findings prompted research groups to dissect the potential functional relevance of NSD2 -inhibition in MM.…”

“…To further define the oncogenic relevance of PHF19 in supporting MM biology, functional studies have been carried out and PHF19 -silencing approaches have demonstrated inhibition of MM cell cycle progression, reduction of MM cell proliferation and survival [ 47 ], thus recapitulating the importance for PHF19 in supporting MM pathogenesis and disease progression. Overall, targeting the PHF19-PRC2-EZH2 complex could represent a novel therapeutic strategy for MM treatment.…”

Artificial Intelligence Effecting a Paradigm Shift in Drug Development

“…This has been demonstrated recently on multiple myeloma (MM), for which a histone methyltransferase, PHF19 , has been identified as the gene with the strongest association with myeloma progression. 78 This potential biomarker was also shown to exhibit greater predictive power than the well-known high-risk gene in MM, MMSET . The platform was also applied on other indications such as metastatic colorectal cancer 79 and Huntington’s disease, for which predictive models were generated based on data from clinical trials.…”

Genetic Predictors of Mortality in Patients with Multiple Myeloma

“…Thus, the overexpression of the HMT PHD finger protein 19 (PHF19) and enhancer of zeste homolog 2 (EZH2) is a strong predictor of poor outcome. 99 , 103 EZH2 is a component of the polycomb repressive complex 2 (PRC2), which tri-methylates histone H3 lysine residue 27 (H3K27me3) to repress gene transcriptome related to stem cell self-renewal, cell cycle checkpoints, metastasis and cellular differentiation. Aberrant activity of EZH2 is regulated at multiple levels driven by interleukin-6 especially in cell lines that harbor K- and N-RAS mutations, 104 upregulation of NF-kB pathway 105 and downregulation of several microRNA (miRNA).…”