Page 213 - Haematologica April 2020

Plasma Cell Disorders
Microhomology-mediated end joining drives complex rearrangements and overexpression of MYC and PVT1 in multiple myeloma
Aneta Mikulasova,1,2 Cody Ashby,1 Ruslana G. Tytarenko,1 Pingping Qu,3 Adam Rosenthal,3 Judith A. Dent,1 Katie R. Ryan,1 Michael A. Bauer,1 Christopher P. Wardell,1 Antje Hoering,3 Konstantinos Mavrommatis,4 Matthew Trotter,5 Shayu Deshpande,1 Shmuel Yaccoby,1 Erming Tian,1 Jonathan Keats,6 Daniel Auclair,7 Graham H. Jackson,8 Faith E. Davies,1 Anjan Thakurta,4 Gareth J. Morgan1 and Brian A. Walker1,9
1Myeloma Center, University of Arkansas for Medical Sciences, Little Rock, AR, USA; 2Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK; 3Cancer Research and Biostatistics, Seattle, WA, USA; 4Celgene Corporation, Summit, NJ, USA; 5Celgene Institute for Translational Research Europe, Seville, Spain; 6Translational Genomics Research Institute, Phoenix, AZ, USA; 7Multiple Myeloma Research Foundation, Norwalk, CT, USA; 8Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK and 9Division of Hematology Oncology, Indiana Univeristy, Indianapolis, IN, USA
ABSTRACT
MYC is a widely acting transcription factor and its deregulation is a crucial event in many human cancers. MYC is important biologically and clinically in multiple myeloma, but the mech- anisms underlying its dysregulation are poorly understood. We show that MYC rearrangements are present in 36.0% of newly diagnosed myeloma patients, as detected in the largest set of next generation sequencing data to date (n=1,267). Rearrangements were complex and associated with increased expression of MYC and PVT1, but not other genes at 8q24. The highest effect on gene expression was detected in cases where the MYC locus is juxtaposed next to super-enhancers asso- ciated with genes such as IGH, IGK, IGL, TXNDC5/BMP6, FAM46C and FOXO3. We identified three hotspots of recombination at 8q24, one of which is enriched for IGH-MYC translocations. Breakpoint analysis indicates primary myeloma rearrangements involving the IGH locus occur through non-homologous end joining, whereas secondary MYC rearrangements occur through microhomology-mediated end joining. This mechanism is different to lymphomas, where non-homologous end joining generates MYC rearrangements. Rearrangements resulted in overexpression of key genes and chromatin immunoprecipitation- sequencing identified that HK2, a member of the glucose metabolism pathway, is directly over-expressed through binding of MYC at its pro- moter.
Introduction
The genome of multiple myeloma (MM) is characterized by primary transloca- tions in approximately 40% of newly diagnosed patients that are considered ini- tiating events and involve rearrangements of the immunoglobulin heavy chain (IGH) locus on 14q32.1 The partners of these rearrangements include 11q (CCND1, 15%), 4p (FGFR3 and MMSET, 10%), 16q (MAF, 2-3%), 20q (MAFB, 1%), and 6q (CCND3, 1%). These rearrangements result in placement of the IGH super- enhancers next to a partner oncogene, resulting in its overexpression.2 The rearrangements predominantly occur in the switch regions 5’ of the constant regions in the IGH locus, where a high concentration of activation-induced cyti- dine deaminase (AID) binding motifs are found. Normally, AID binds to the switch regions leading to class switch recombination, resulting in antibody isotype
Ferrata Storti Foundation
Haematologica 2020 Volume 105(4):1055-1066
Correspondence:
BRIAN A. WALKER
bw75@iu.edu
Received: January 29, 2019. Accepted: June 13, 2019. Pre-published: June 20, 2019.
doi:10.3324/haematol.2019.217927
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/105/4/1055
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