Perturbations of transcriptional regulation and chromatin structuring play a fundamental role in malignant transformation. Mutations and disruptions in epigenetic regulators are among the lesions commonly found in multiple myeloma (MM) and will be addressed in detail in this session.
Dr. Jonathan Licht will discuss epigenetic regulators in MM and how to provide therapeutic avenues in MM. He will specifically focus on one of the most common anomalies of epigenetic regulators in MM, which is the overexpression of NSD2/MMSET resulting from its fusion to the immunoglobulin locus in t (4;14). This chromatin modification is associated with active genes and prevents the action of the repressive HMT, EZH2 thus resulting in aberrant gene expression, enhanced cell growth, altered responses to DNA damage, and resistance to chemotherapy.
Dr. Paola Neri will discuss enhancer deregulation in MM and promising therapeutic options for this disease. Immunoglobulin and non-immunoglobulin enhancers’ hijacking by variable genes is a recognized oncogenic driver event in MM. In addition, promiscuous rearrangements of the Myc locus is known to hijack enhancers and super-enhancers to dysregulate Myc expression in MM and are involved in its pathogenesis. Dr. Neri will discuss how the Bromodomain and Extra-Terminal Domain family member, BRD4, (a master histone acetyl marker reader at enhancers loci regulating) Myc, has led to promising therapeutic developments in MM and numerous other cancers.
Dr. Gareth Morgan will define the clinical application of epigenetic modifier mutations in MM. Epigenetic mutations/alterations found in next generation sequencing studies have been used to define prognostic relevance and outcome in patients with MM. Scanning the spectrum of mutations that are therapeutically tractable shows that rare cases may benefit from entry into basket studies investigating epigenetically active agents. Dr. Morgan will discuss how the association between acquired structural events within the non-coding genome, 3D chromatin structure, and altered gene expression opens the possibility of using a spectrum of epigenetic agents to control super-enhancer-driven transactivation domain deregulation and abnormal oncogene expression.
Jonathan Licht, MD
Paola Neri, MD
Gareth Morgan, MD, PhD
Active, International, Emeritus, and Honorary Members
Associate, International Associate, Student, and Resident Members