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

Affer M, Chesi M, Chen WD, Keats JJ, Demchenko YN, Tamizhmani K, Garbitt VM, Riggs DL, Brents LA, Roschke AV, Van Wier S, Fonseca R, Bergsagel PL, Kuehl WM - Leukemia (2014)

Bottom Line: 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.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).Our data suggest that MYC rearrangements, regardless of when they occur during MM pathogenesis, provide one event that contributes to tumor autonomy.

View Article: PubMed Central - PubMed

Affiliation: Department of Hematology Oncology, Mayo Clinic Arizona, Comprehensive Cancer Center, Scottsdale, AZ, USA.

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 (monoclonal gammopathy of undetermined significance)-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 biallelic MYC expression at significantly higher levels than in MGUS. We also have shown 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 biallelic, but sometimes can be monoallelic if there is an MYC rearrangement. Our data suggest that MYC rearrangements, regardless of when they occur during MM pathogenesis, provide one event that contributes to tumor autonomy.

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MYC locus rearrangements in 16 MMCL and 12 MMRC tumorsA. The anatomy of MYC locus rearrangements on chr8 (light green) shows MM.1S enhancers and super enhancers, and duplicated regions, with the genes associated with the enhancer regions indicated at the left. Enhancer elements in the MYC locus are not shown here but are shown in Figure 4. The orientations of the chromosomes and transcription units are indicated. The white arrowheads indicate intrachromosomal breakpoints, with the pair of white arrows in XG6 and H929 indicating a deletion, the pair of arrows in U266 and LP1 indicating an inversion, and the single white arrow in ARP1, KP6, and XG2 indicating tandem duplication. A more detailed diagram of the XG6 and LP1 rearrangements is shown in Figure S1. Additional information regarding these rearrangements is included in Results and Table S10.B. The anatomy of MYC locus rearrangements for 12 MMRC tumors is presented as described in Figure 3. Several of the MM tumors have two different rearrangements. Additional information regarding these rearrangements is summarized in Results, Table 2, and Table S11.C. cIg-FISH was performed in MMRC0408 demonstrating co-localization of probes for MYC (red) and the IgJ enhancer (green) in the nuclei of plasma cells with light chain restriction (blue cytoplasmic staining).
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Figure 3: MYC locus rearrangements in 16 MMCL and 12 MMRC tumorsA. The anatomy of MYC locus rearrangements on chr8 (light green) shows MM.1S enhancers and super enhancers, and duplicated regions, with the genes associated with the enhancer regions indicated at the left. Enhancer elements in the MYC locus are not shown here but are shown in Figure 4. The orientations of the chromosomes and transcription units are indicated. The white arrowheads indicate intrachromosomal breakpoints, with the pair of white arrows in XG6 and H929 indicating a deletion, the pair of arrows in U266 and LP1 indicating an inversion, and the single white arrow in ARP1, KP6, and XG2 indicating tandem duplication. A more detailed diagram of the XG6 and LP1 rearrangements is shown in Figure S1. Additional information regarding these rearrangements is included in Results and Table S10.B. The anatomy of MYC locus rearrangements for 12 MMRC tumors is presented as described in Figure 3. Several of the MM tumors have two different rearrangements. Additional information regarding these rearrangements is summarized in Results, Table 2, and Table S11.C. cIg-FISH was performed in MMRC0408 demonstrating co-localization of probes for MYC (red) and the IgJ enhancer (green) in the nuclei of plasma cells with light chain restriction (blue cytoplasmic staining).

Mentions: The structures of rearrangements involving MYC (or MYCL) in 17 MMCL (Figure 3A, Table 2, Table S10) were deduced from a combination of FISH, CGH, and mate pair or cloned sequences. We also indicate enhancer elements repositioned near the MYC locus, using published reference data for two cell lines: 1) enhancers and super enhancers (SEs) in the MM.1S MMCL34, 35; and 2) strong enhancers and stretch enhancers identified in the GM12878 lymphoblastoid cell line (LCL), which is phenotypically similar to MMCL, from ENCODE data on the UCSC genome browser (http://genome.ucsc.edu)36 and Parker et al37. Although the enhancers and SEs in these two cell lines might not apply to all MMCL and tumors, we have additional evidence suggesting that they generally are applicable. First, most of the putative SEs associated with MYC locus rearrangements (Tables 2 and 3; DISCUSSION) have been shown to be markedly up-regulated with differentiation of B cells to plasma cells (Figure 2E)23. Second, we have preliminary DNaseI HS.seq and ChIP.seq (H3K4Me3; H3K27Ac) data for 4 MMCL that identify the same enhancers and putative SEs that were identified in the MM.1S MMCL. A description of the structures of rearrangements involving MYC in 12 MMRC tumors, which were deduced mostly from whole genome sequences,38 but also from FISH, CGH, and cloned sequences in some cases, is presented in Table 3 and Figure 3B, with additional details in Table S11.


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

Affer M, Chesi M, Chen WD, Keats JJ, Demchenko YN, Tamizhmani K, Garbitt VM, Riggs DL, Brents LA, Roschke AV, Van Wier S, Fonseca R, Bergsagel PL, Kuehl WM - Leukemia (2014)

MYC locus rearrangements in 16 MMCL and 12 MMRC tumorsA. The anatomy of MYC locus rearrangements on chr8 (light green) shows MM.1S enhancers and super enhancers, and duplicated regions, with the genes associated with the enhancer regions indicated at the left. Enhancer elements in the MYC locus are not shown here but are shown in Figure 4. The orientations of the chromosomes and transcription units are indicated. The white arrowheads indicate intrachromosomal breakpoints, with the pair of white arrows in XG6 and H929 indicating a deletion, the pair of arrows in U266 and LP1 indicating an inversion, and the single white arrow in ARP1, KP6, and XG2 indicating tandem duplication. A more detailed diagram of the XG6 and LP1 rearrangements is shown in Figure S1. Additional information regarding these rearrangements is included in Results and Table S10.B. The anatomy of MYC locus rearrangements for 12 MMRC tumors is presented as described in Figure 3. Several of the MM tumors have two different rearrangements. Additional information regarding these rearrangements is summarized in Results, Table 2, and Table S11.C. cIg-FISH was performed in MMRC0408 demonstrating co-localization of probes for MYC (red) and the IgJ enhancer (green) in the nuclei of plasma cells with light chain restriction (blue cytoplasmic staining).
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Figure 3: MYC locus rearrangements in 16 MMCL and 12 MMRC tumorsA. The anatomy of MYC locus rearrangements on chr8 (light green) shows MM.1S enhancers and super enhancers, and duplicated regions, with the genes associated with the enhancer regions indicated at the left. Enhancer elements in the MYC locus are not shown here but are shown in Figure 4. The orientations of the chromosomes and transcription units are indicated. The white arrowheads indicate intrachromosomal breakpoints, with the pair of white arrows in XG6 and H929 indicating a deletion, the pair of arrows in U266 and LP1 indicating an inversion, and the single white arrow in ARP1, KP6, and XG2 indicating tandem duplication. A more detailed diagram of the XG6 and LP1 rearrangements is shown in Figure S1. Additional information regarding these rearrangements is included in Results and Table S10.B. The anatomy of MYC locus rearrangements for 12 MMRC tumors is presented as described in Figure 3. Several of the MM tumors have two different rearrangements. Additional information regarding these rearrangements is summarized in Results, Table 2, and Table S11.C. cIg-FISH was performed in MMRC0408 demonstrating co-localization of probes for MYC (red) and the IgJ enhancer (green) in the nuclei of plasma cells with light chain restriction (blue cytoplasmic staining).
Mentions: The structures of rearrangements involving MYC (or MYCL) in 17 MMCL (Figure 3A, Table 2, Table S10) were deduced from a combination of FISH, CGH, and mate pair or cloned sequences. We also indicate enhancer elements repositioned near the MYC locus, using published reference data for two cell lines: 1) enhancers and super enhancers (SEs) in the MM.1S MMCL34, 35; and 2) strong enhancers and stretch enhancers identified in the GM12878 lymphoblastoid cell line (LCL), which is phenotypically similar to MMCL, from ENCODE data on the UCSC genome browser (http://genome.ucsc.edu)36 and Parker et al37. Although the enhancers and SEs in these two cell lines might not apply to all MMCL and tumors, we have additional evidence suggesting that they generally are applicable. First, most of the putative SEs associated with MYC locus rearrangements (Tables 2 and 3; DISCUSSION) have been shown to be markedly up-regulated with differentiation of B cells to plasma cells (Figure 2E)23. Second, we have preliminary DNaseI HS.seq and ChIP.seq (H3K4Me3; H3K27Ac) data for 4 MMCL that identify the same enhancers and putative SEs that were identified in the MM.1S MMCL. A description of the structures of rearrangements involving MYC in 12 MMRC tumors, which were deduced mostly from whole genome sequences,38 but also from FISH, CGH, and cloned sequences in some cases, is presented in Table 3 and Figure 3B, with additional details in Table S11.

Bottom Line: 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.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).Our data suggest that MYC rearrangements, regardless of when they occur during MM pathogenesis, provide one event that contributes to tumor autonomy.

View Article: PubMed Central - PubMed

Affiliation: Department of Hematology Oncology, Mayo Clinic Arizona, Comprehensive Cancer Center, Scottsdale, AZ, USA.

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 (monoclonal gammopathy of undetermined significance)-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 biallelic MYC expression at significantly higher levels than in MGUS. We also have shown 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 biallelic, but sometimes can be monoallelic if there is an MYC rearrangement. Our data suggest that MYC rearrangements, regardless of when they occur during MM pathogenesis, provide one event that contributes to tumor autonomy.

Show MeSH
Related in: MedlinePlus