MYC dysregulation in the progression of multiple myeloma

Abstract

Multiple myeloma (MM) is a plasma cell malignancy preceded by a premalignant stage, named monoclonal gammopathy of undetermined significance (MGUS), and often a smoldering phase (SMM). 1, 2 Primary events, which include recurrent translocations of the IgH locus and hyperdiploidy, occur early in pathogenesis, and are followed by the acquisition of secondary genetic events such as MYC structural variants (SV), mutations that activate the RAS or NFkB pathways, mutations of DIS3 or FAM46C that drive precursor stages of disease toward MM. [3][4][5][6] Whole exome sequencing (WES) studies comparing serial MGUS/SMM and MM samples indicate clonal stability, and no significant increase in mutational load in patients that progress rapidly to MM. 7 In contrast, in 33 unselected MGUS patients single-nucleotide variants (SNVs) were less frequent, and no MYC translocations identified. 8 To study the role of MYC in myeloma we performed an integrated genomic analysis of 612 newly diagnosed myeloma (NDMM) patients enrolled in the CoMMpass study, as well as Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms * shared first co-authors Authorship Contributions PLB, WMK and KM originated concept and design of investigation, KMK EB developed custom capture panel, SVW FISH analysis, GA primary samples, YA GD WMK PLB developed additional bioinformatics methods, NK KM CKS PLB WMK performed analyses, and NK KM CKS WMK PLB composed manuscript. We thank JK and MMRF research network for their work on CoMMpass. All authors read and approved of final manuscript. Conflict of Interest DisclosuresRafael Fonseca works as a consultant for AMGEN, BMS, Celgene, Takeda, Bayer, Jansen, Pharmacyclics, Merck, Sanofi, Kite and Juno. He is on the board of Scientific Advisory Board: Adaptive Biotechnologies. Mayo Clinic and Rafael Fonseca hold a patent for prognosticating myeloma using FISH.

Accelerated single cell seeding in relapsed multiple myeloma

“…5,6 Divergence and progression at distinct sites of disease -spatial evolution -magnifies the genomic heterogeneity of multiple myeloma, where a range of clones compete for dominance and are positively selected according to their genetic driver landscape reflected in their ability to best adapt to the local environment. [7][8][9][10][11][12] Similar evolutionary patterns have also been observed in patients with multiple myeloma at clinical relapse. 13,14 However, it is unclear if, at the time of relapse, the new disease sites reflect a pre-existing but previously undetected disease localization or a new dissemination of disease "seeding".…”

Targeting of the E3 ubiquitin-protein ligase HUWE1 impairs DNA repair capacity and tumor growth in preclinical multiple myeloma models

“…Unlike its role in colon cancer, our data thus do not imply HUWE1 as important regulator of MYC activity in MM. However, our results are compatible with recent in-depth analyses of the genetic mechanisms of MYC dysregulation in MM, which suggest that—unlike in other cancer entities— MYC expression is not correlated with proliferation but may rather support other physiological needs of plasma cell tumors 19 .…”

Next-Generation Sequencing for Clinical Management of Multiple Myeloma: Ready for Prime Time?

“…This has been particularly fruitful in the case of MYC rearrangements, which are frequent in MM but hard to study due to promiscuous partners and distant breakpoints. A recent study has clarified how only IGH-MYC rearrangements confer high-risk of SMM progression, mandating that risk scores are updated to reflect this analysis (94). Also complex rearrangements, a newly discovered phenomenon in MM (23), were equally present in SMM albeit at a lower cancer cell fraction (32).…”