Microhomology-mediated end joining drives complex rearrangements and overexpression of MYC and PVT1 in multiple myeloma
Aneta Mikulasova,
Cody Ashby,
Ruslana G. Tytarenko,
Pingping Qu,
Adam Rosenthal,
Judith A. Dent,
Katie R. Ryan,
Michael A. Bauer,
Christopher P. Wardell,
Antje Hoering,
Konstantinos Mavrommatis,
Matthew Trotter,
Shayu Deshpande,
Shmuel Yaccoby,
Erming Tian,
Jonathan Keats,
Daniel Auclair,
Graham H. Jackson,
Faith E. Davies,
Anjan Thakurta,
Gareth J. Morgan,
Brian A. Walker
Affiliations
Aneta Mikulasova
Myeloma Center, University of Arkansas for Medical Sciences, Little Rock, AR, USA;Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK
Cody Ashby
Myeloma Center, University of Arkansas for Medical Sciences, Little Rock, AR, USA
Ruslana G. Tytarenko
Myeloma Center, University of Arkansas for Medical Sciences, Little Rock, AR, USA
Pingping Qu
Cancer Research and Biostatistics, Seattle, WA, USA
Adam Rosenthal
Cancer Research and Biostatistics, Seattle, WA, USA
Judith A. Dent
Myeloma Center, University of Arkansas for Medical Sciences, Little Rock, AR, USA
Katie R. Ryan
Myeloma Center, University of Arkansas for Medical Sciences, Little Rock, AR, USA
Michael A. Bauer
Myeloma Center, University of Arkansas for Medical Sciences, Little Rock, AR, USA
Christopher P. Wardell
Myeloma Center, University of Arkansas for Medical Sciences, Little Rock, AR, USA
Antje Hoering
Cancer Research and Biostatistics, Seattle, WA, USA
Konstantinos Mavrommatis
Celgene Corporation, Summit, NJ, USA
Matthew Trotter
Celgene Institute for Translational Research Europe, Seville, Spain
Shayu Deshpande
Myeloma Center, University of Arkansas for Medical Sciences, Little Rock, AR, USA
Shmuel Yaccoby
Myeloma Center, University of Arkansas for Medical Sciences, Little Rock, AR, USA
Erming Tian
Myeloma Center, University of Arkansas for Medical Sciences, Little Rock, AR, USA
Jonathan Keats
Translational Genomics Research Institute, Phoenix, AZ, USA
Daniel Auclair
Multiple Myeloma Research Foundation, Norwalk, CT, USA
Graham H. Jackson
Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK
Faith E. Davies
Myeloma Center, University of Arkansas for Medical Sciences, Little Rock, AR, USA
Anjan Thakurta
Celgene Corporation, Summit, NJ, USA
Gareth J. Morgan
Myeloma Center, University of Arkansas for Medical Sciences, Little Rock, AR, USA
Brian A. Walker
Myeloma Center, University of Arkansas for Medical Sciences, Little Rock, AR, USA;Division of Hematology Oncology, Indiana Univeristy, Indianapolis, IN, USA
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 mechanisms 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 associated 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 promoter.
