Promiscuous MYC locus rearrangements hijack enhancers but mostly super-enhancers to dysregulate MYC expression in multiple myeloma

Abstract

MYC locus rearrangements – often complex combinations of translocations, insertions, deletions, and inversions - in multiple myeloma (MM) were thought to be a late progression event, which often did not involve immunoglobulin genes. Yet germinal center activation of MYC expression has been reported to cause progression to MM in an MGUS prone mouse strain. Although previously detected in 16% of MM, we find MYC rearrangements in nearly 50% of MM, including smoldering MM, and they are heterogeneous in some cases. Rearrangements reposition MYC near a limited number of genes associated with conventional enhancers, but mostly with super-enhancers (e.g., IGH, IGL, IGK, NSMCE2, TXNDC5, FAM46C, FOXO3, IGJ, PRDM1). MYC rearrangements are associated with a significant increase of MYC expression that is monoallelic, but MM tumors lacking a rearrangement have bi-allelic MYC expression at significantly higher levels than in MGUS. We also show that germinal center activation of MYC does not cause MM in a mouse strain that rarely develops spontaneous MGUS. It appears that increased MYC expression at the MGUS/MM transition usually is bi-allelic, but sometimes can be mono-allelic if there is a MYC rearrangement. Our data suggests that MYC rearrangements, regardless of when they occur during MM pathogenesis, provide one event that contributes to tumor autonomy.

Concomitant gain of 1q21 and MYC translocation define a poor prognostic subgroup of hyperdiploid multiple myeloma

“…1,2 Desiree Kirn, 3 Anja Seckinger, 1 Thomas Hielscher, 4 Martin Granzow, 3 Uta Bertsch, 1 Gerlinde Egerer, 1 Hans Salwender, 5 Igor W. Blau,…”

“…Altogether, 153 patients (55.8%) showed MYC aberrations, confirming the results of a study that used FISH and comparative genomic hybridization and detected MYC aberrations iñ 50% of MM patients. 4 A t(MYC) (34%), +MYC (50%) and del(MYC) (83%) frequently occurred in subclones only, indicating they are often not initiating events.…”

“…In contrast, t(MYC) was not depleted in HDMM in our set, but rather showed a higher frequency. One possible explanation for © Ferrata Storti Foundation these discrepancies was stated by Affer et al 4 Due to the high material requirements in the case of multiple molecular analyses, samples may be biased for larger tumor mass or aggressive clones. In the GMMG-HD4 trial, the processing of MM samples for FISH analyses had priority, and we included all patients in our study for whom FISH slides were available.…”

MYC as therapeutic target in leukemia and lymphoma

“…Rearrangements of the MYC oncogene are present in 15%-50% of primary human multiple myelomas (MMs), in many cases involved in complex rearrangements, 57,58 and its activation seems to play a role in the progression of plasma cell neoplasms, particularly from monoclonal gammopathy of undetermined signif icance (MGUS) to plasma cell myeloma. Indeed, MYC rearrangements and overexpression are more frequent in MM than in MGUS 57,59,60 and mark a more aggressive disease.…”

Systematic analysis of berberine-induced signaling pathway between miRNA clusters and mRNAs and identification of mir-99a∼125b cluster function by seed-targeting inhibitors in multiple myeloma cells

“…These data suggest that Myc rearrangements, regardless of when they occur during MM pathogenesis, contribute to tumor autonomy. 30 miRNAs from the mir-99a»125b cluster are transcribed together on the same miRNA polycistron, and are over-expressed in multiple hematological malignancies. The mir-99a»125b cluster is able to function as an oncomir in leukemia 31,32 and prostate cancer.…”