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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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Three chromosomal regions involved in recurrent MYC rearrangementsSymbols at the top apply to Panels A-D; the boxed symbols at the bottom to Panel D.A. Large deletions (blue lines) identified by Agilent 244K CGH results in 53 MMCL and 218 MMRC tumors indicates a repositioning of MYC near enhancers associated with NSMCE2 and TRIB1, which are located about 2.5 Mb centromeric to MYC. The dark red boxes indicate regions of copy number gains that flank the deleted regions. Breakpoints have been identified by sequencing or mate pairs in two MMCL (H929, XG6) and in one of the tumors (MMRC0392) shown in this figure, but also in two other tumors (MMRC0375, 0421) with complex CGH patterns not shown in this Figure.B. Super enhancers associated with TXNDC5 on chr6. The red lines indicate regions of copy number gains determined from 244K CGH data on MMCL and 218 MMRC tumors. The copy number gain is juxtaposed near MYC in three MMCL (KMS18, OCIMY1, XG7) and one tumor (MMRC406) and near SUSD2 in the JIM3 MMCL. The copy number gains shown are significantly enriched in MMRC tumors that have MYC rearrangements not involving IGH or IGL loci (see DISCUSSION).C. Segmental copy number gains localized >200 kb telomeric to MYC. MMCL and MMRC tumors with segmental copy number gains (red lines) identified from Agilent 244K CGH data are shown. Many of these gains flank insertions of enhancer elements (see Results and Discussion), or occur in tumors or MMCL that have MYC.IGH or MYC.IGL fusion signals. Most of these gains are centered in two regions that are about 350 kb and 500 kb downstream of MYC. The former occurs within the distal end of the PVT1 locus, near one MM.1S enhancer and multiple LCL enhancers. The latter is centered in a region that preferentially associates with the MYC promoter, but also contains a cluster of MM.1S enhancer sequences and GM12878 stretch enhancers.D. Interaction of MYC promoter with distal telomeric sequences. 3C experiments show a preferential interaction of a MYC promoter fragment that contains a CTCF site with a fragment, which is located ~500 kb telomeric of MYC, that also contains a CTCF sequence. The JJN3 MMCL has a MYC:IGH rearrangement, but the U266 MMCL has a MYCL rearrangement and expresses virtually no MYC.
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Figure 4: Three chromosomal regions involved in recurrent MYC rearrangementsSymbols at the top apply to Panels A-D; the boxed symbols at the bottom to Panel D.A. Large deletions (blue lines) identified by Agilent 244K CGH results in 53 MMCL and 218 MMRC tumors indicates a repositioning of MYC near enhancers associated with NSMCE2 and TRIB1, which are located about 2.5 Mb centromeric to MYC. The dark red boxes indicate regions of copy number gains that flank the deleted regions. Breakpoints have been identified by sequencing or mate pairs in two MMCL (H929, XG6) and in one of the tumors (MMRC0392) shown in this figure, but also in two other tumors (MMRC0375, 0421) with complex CGH patterns not shown in this Figure.B. Super enhancers associated with TXNDC5 on chr6. The red lines indicate regions of copy number gains determined from 244K CGH data on MMCL and 218 MMRC tumors. The copy number gain is juxtaposed near MYC in three MMCL (KMS18, OCIMY1, XG7) and one tumor (MMRC406) and near SUSD2 in the JIM3 MMCL. The copy number gains shown are significantly enriched in MMRC tumors that have MYC rearrangements not involving IGH or IGL loci (see DISCUSSION).C. Segmental copy number gains localized >200 kb telomeric to MYC. MMCL and MMRC tumors with segmental copy number gains (red lines) identified from Agilent 244K CGH data are shown. Many of these gains flank insertions of enhancer elements (see Results and Discussion), or occur in tumors or MMCL that have MYC.IGH or MYC.IGL fusion signals. Most of these gains are centered in two regions that are about 350 kb and 500 kb downstream of MYC. The former occurs within the distal end of the PVT1 locus, near one MM.1S enhancer and multiple LCL enhancers. The latter is centered in a region that preferentially associates with the MYC promoter, but also contains a cluster of MM.1S enhancer sequences and GM12878 stretch enhancers.D. Interaction of MYC promoter with distal telomeric sequences. 3C experiments show a preferential interaction of a MYC promoter fragment that contains a CTCF site with a fragment, which is located ~500 kb telomeric of MYC, that also contains a CTCF sequence. The JJN3 MMCL has a MYC:IGH rearrangement, but the U266 MMCL has a MYCL rearrangement and expresses virtually no MYC.

Mentions: Figure 4 summarizes CGH CNA and breakpoints in two recurrent non-IG partner loci. First, it is not surprising that centromeric losses – and perhaps some gains (not shown) - that juxtapose MYC and NSMCE2/TRIB1 enhancers were the most common MYC:nonIG rearrangement since intra-chromosomal rearrangements are more common than inter-chromosomal rearrangements39 (Figure 4A). Second, in addition to the three MMCL and two MM tumors with MYC:TXNDC5 rearrangements, Figure 4B shows other MMCL and MM tumors with gains involving TXNDC5, which are clustered among tumors with CGH detected MYC rearrangements not involving IGH or IGL compared to tumors that have a MYC:IGH or MYC:IGL rearrangement or no rearrangement (P=0.0001).


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)

Three chromosomal regions involved in recurrent MYC rearrangementsSymbols at the top apply to Panels A-D; the boxed symbols at the bottom to Panel D.A. Large deletions (blue lines) identified by Agilent 244K CGH results in 53 MMCL and 218 MMRC tumors indicates a repositioning of MYC near enhancers associated with NSMCE2 and TRIB1, which are located about 2.5 Mb centromeric to MYC. The dark red boxes indicate regions of copy number gains that flank the deleted regions. Breakpoints have been identified by sequencing or mate pairs in two MMCL (H929, XG6) and in one of the tumors (MMRC0392) shown in this figure, but also in two other tumors (MMRC0375, 0421) with complex CGH patterns not shown in this Figure.B. Super enhancers associated with TXNDC5 on chr6. The red lines indicate regions of copy number gains determined from 244K CGH data on MMCL and 218 MMRC tumors. The copy number gain is juxtaposed near MYC in three MMCL (KMS18, OCIMY1, XG7) and one tumor (MMRC406) and near SUSD2 in the JIM3 MMCL. The copy number gains shown are significantly enriched in MMRC tumors that have MYC rearrangements not involving IGH or IGL loci (see DISCUSSION).C. Segmental copy number gains localized >200 kb telomeric to MYC. MMCL and MMRC tumors with segmental copy number gains (red lines) identified from Agilent 244K CGH data are shown. Many of these gains flank insertions of enhancer elements (see Results and Discussion), or occur in tumors or MMCL that have MYC.IGH or MYC.IGL fusion signals. Most of these gains are centered in two regions that are about 350 kb and 500 kb downstream of MYC. The former occurs within the distal end of the PVT1 locus, near one MM.1S enhancer and multiple LCL enhancers. The latter is centered in a region that preferentially associates with the MYC promoter, but also contains a cluster of MM.1S enhancer sequences and GM12878 stretch enhancers.D. Interaction of MYC promoter with distal telomeric sequences. 3C experiments show a preferential interaction of a MYC promoter fragment that contains a CTCF site with a fragment, which is located ~500 kb telomeric of MYC, that also contains a CTCF sequence. The JJN3 MMCL has a MYC:IGH rearrangement, but the U266 MMCL has a MYCL rearrangement and expresses virtually no MYC.
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Figure 4: Three chromosomal regions involved in recurrent MYC rearrangementsSymbols at the top apply to Panels A-D; the boxed symbols at the bottom to Panel D.A. Large deletions (blue lines) identified by Agilent 244K CGH results in 53 MMCL and 218 MMRC tumors indicates a repositioning of MYC near enhancers associated with NSMCE2 and TRIB1, which are located about 2.5 Mb centromeric to MYC. The dark red boxes indicate regions of copy number gains that flank the deleted regions. Breakpoints have been identified by sequencing or mate pairs in two MMCL (H929, XG6) and in one of the tumors (MMRC0392) shown in this figure, but also in two other tumors (MMRC0375, 0421) with complex CGH patterns not shown in this Figure.B. Super enhancers associated with TXNDC5 on chr6. The red lines indicate regions of copy number gains determined from 244K CGH data on MMCL and 218 MMRC tumors. The copy number gain is juxtaposed near MYC in three MMCL (KMS18, OCIMY1, XG7) and one tumor (MMRC406) and near SUSD2 in the JIM3 MMCL. The copy number gains shown are significantly enriched in MMRC tumors that have MYC rearrangements not involving IGH or IGL loci (see DISCUSSION).C. Segmental copy number gains localized >200 kb telomeric to MYC. MMCL and MMRC tumors with segmental copy number gains (red lines) identified from Agilent 244K CGH data are shown. Many of these gains flank insertions of enhancer elements (see Results and Discussion), or occur in tumors or MMCL that have MYC.IGH or MYC.IGL fusion signals. Most of these gains are centered in two regions that are about 350 kb and 500 kb downstream of MYC. The former occurs within the distal end of the PVT1 locus, near one MM.1S enhancer and multiple LCL enhancers. The latter is centered in a region that preferentially associates with the MYC promoter, but also contains a cluster of MM.1S enhancer sequences and GM12878 stretch enhancers.D. Interaction of MYC promoter with distal telomeric sequences. 3C experiments show a preferential interaction of a MYC promoter fragment that contains a CTCF site with a fragment, which is located ~500 kb telomeric of MYC, that also contains a CTCF sequence. The JJN3 MMCL has a MYC:IGH rearrangement, but the U266 MMCL has a MYCL rearrangement and expresses virtually no MYC.
Mentions: Figure 4 summarizes CGH CNA and breakpoints in two recurrent non-IG partner loci. First, it is not surprising that centromeric losses – and perhaps some gains (not shown) - that juxtapose MYC and NSMCE2/TRIB1 enhancers were the most common MYC:nonIG rearrangement since intra-chromosomal rearrangements are more common than inter-chromosomal rearrangements39 (Figure 4A). Second, in addition to the three MMCL and two MM tumors with MYC:TXNDC5 rearrangements, Figure 4B shows other MMCL and MM tumors with gains involving TXNDC5, which are clustered among tumors with CGH detected MYC rearrangements not involving IGH or IGL compared to tumors that have a MYC:IGH or MYC:IGL rearrangement or no rearrangement (P=0.0001).

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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Related in: MedlinePlus