The research laboratory directed by Dr. Greg Wang, associate professor of the Department of Biochemistry and Biophysics and the Cancer Cell Biology Program at the Lineberger Comprehensive Cancer Center, University of North Carolina (UNC) at Chapel Hill, recently identified a gene termed PHF19 to be critically involved in the development and progression of multiple myeloma, and also provided proof-of-principle evidence supporting pharmacological targeting of this pathway for therapeutics of this common hematological cancer. These findings were recently published by BLOOD, the official journal of the American Society of Hematology.
Multiple myeloma (MM) is a malignant disease derived from plasma cells, the cell’s “factory” generating antibodies for hosts fighting against evading pathogens. MM is the second most prevalent (composing for 10%) of all hematological malignancies and will account for 32,110 new cases and 12,960 death in the U.S. in 2019 based on the American Cancer Society’s statistics. While the incidence of MM is taking an upward trend worldwide, the hard truth is a lack of no regimens to cure this malignant tumor, besides bone marrow/hematopoietic stem cell transplantation and drugs including the recently FDA-approved ones. It is imperative to find new treatment regimens and drug targets for patients with MM, since transplants are not an option for the majority of them because of their generally advanced age and the scarcity of HLA matched donors.
Dr. Wang’s research team begun their quest by mining of available transcriptome datasets from several independently carried-out clinical trials, searching for association of gene signatures with clinic outcomes. PHF19, a gene previously studied by the Wang laboratory (Mol Cell. 2013 Feb 7;49(3):571-82), caught attention – high expression levels of the PHF19 gene are correlated with poorer prognosis across all six datasets from independent clinical trials composed cumulatively of more than 1,500 patient cases.
“The odds to have got it by chance would be less than 2×10-10, even with the most conservative estimation”, said Dr. Zhihong Ren, a postdoc researcher fellow.
As an expert in epigenetics/genetics of hematological malignancies, Dr. Wang’s team has previously shown a functional linkage between PHF19 and a so-called Polycomb Repressive Complex 2 (PRC2). Using state-of-the-art gene loss-of-function techniques, Dr. Ren demonstrated the dependence of various MM models on PHF19 protein in malignant progression of the disease. Using RNA-seq, ChIP-seq and proteomics techniques, the researchers from Dr. Wang’s team and collaborators characterized the PHF19-dependent transcriptional programs in myeloma cells, and most importantly, provided evidence to show that PHF19 acts through PRC2 hyper-activation in tumorigenesis of myeloma. PRC2 can be druggable by a small-molecule inhibitor termed as UNC1999, initially developed at UNC by Dr. Jian Jin, a coauthor of the study. In this work, Dr. Wang’s team provided UNC1999 treatment results showing early promise for PRC2 blockade as a new therapeutics of MM in the laboratory models. “Unlike those genetic mutations, epigenetic abnormalities of human tumors are sort of a software malfunction, instead of hardware breakage. Epigenetic alterations are more amenable to therapeutic interventions with the targeted compounds”, Said Dr. Wang, whose lab has been focused on targeting epigenetic machineries as way for treating human tumors.