RT Journal Article
SR Electronic
T1 Microhomology-mediated end joining drives complex rearrangements and over-expression of <em>MYC</em> and <em>PVT1</em> in multiple myeloma
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 515106
DO 10.1101/515106
A1 Aneta Mikulasova
A1 Cody Ashby
A1 Ruslana G. Tytarenko
A1 Pingping Qu
A1 Adam Rosenthal
A1 Judith A. Dent
A1 Katie R. Ryan
A1 Michael A. Bauer
A1 Christopher P. Wardell
A1 Antje Hoering
A1 Konstantinos Mavrommatis
A1 Matthew Trotter
A1 Shayu Deshpande
A1 Shmuel Yaccoby
A1 Erming Tian
A1 Jonathan Keats
A1 Daniel Auclair
A1 Graham H. Jackson
A1 Faith E. Davies
A1 Anjan Thakurta
A1 Gareth J. Morgan
A1 Brian A. Walker
YR 2019
UL http://biorxiv.org/content/early/2019/06/24/515106.abstract
AB 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=1267). 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 over-expression of key genes and ChIP-seq identified that HK2, a member of the glucose metabolism pathway, is directly over-expressed through binding of MYC at its promoter.