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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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Copy number abnormalities in the MYC locus in MM tumors and cell linesSegmented Agilent 244k aCGH of the MYC locus (chr8: 126000000-130000000) in 101 of 238 MM tumors and 42 of 53 MMCL with CNA viewed in IGV is shown. The overall copy number for the region for each sample has been normalized to two copies in order to highlight local changes in copy number. More then a one log gain is deep red, more then one log loss is deep blue, and copy number within 0.2 log of diploid is white. The samples are ordered starting with telomeric deletions, segmental telomeric gains (blue arrowhead), segmental MYC gains (black arrowhead) and centromeric deletions and/or gains.
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Figure 1: Copy number abnormalities in the MYC locus in MM tumors and cell linesSegmented Agilent 244k aCGH of the MYC locus (chr8: 126000000-130000000) in 101 of 238 MM tumors and 42 of 53 MMCL with CNA viewed in IGV is shown. The overall copy number for the region for each sample has been normalized to two copies in order to highlight local changes in copy number. More then a one log gain is deep red, more then one log loss is deep blue, and copy number within 0.2 log of diploid is white. The samples are ordered starting with telomeric deletions, segmental telomeric gains (blue arrowhead), segmental MYC gains (black arrowhead) and centromeric deletions and/or gains.

Mentions: Fifty-three independent MMCL were analyzed for MYC locus rearrangements by metaphase FISH assays as described previously.10 Including two MMCL that express MYCL or MYCN, MYC rearrangements involving a MYC family member were detected in 42/53 (79%) MMCL (Table S1, Table S2). Most rearrangements were complex translocations or insertions. The 244K Agilent array CGH platform also detected MYC locus (but not MYCL or MYCN) copy number abnormalities (CNA) identifying unbalanced rearrangements in 42/53 (79%) MMCL, including five for which rearrangements were not detected by the karyotypic assays (Figure 1,Table S1, Table S2). No MYC locus rearrangements were detected by either assay in 6/53 (11%) of MMCL. Twenty-eight of the 47 MMCL with MYC rearrangements repositioned a MYC family member near one of the IG 3’ enhancer sequences that are included in the FISH probes: 21 with IGH, 5 with IGL, and 2 with IGK (Table S2). Rearrangements in the remaining 19 MMCL did not reveal recurrent partner loci.


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)

Copy number abnormalities in the MYC locus in MM tumors and cell linesSegmented Agilent 244k aCGH of the MYC locus (chr8: 126000000-130000000) in 101 of 238 MM tumors and 42 of 53 MMCL with CNA viewed in IGV is shown. The overall copy number for the region for each sample has been normalized to two copies in order to highlight local changes in copy number. More then a one log gain is deep red, more then one log loss is deep blue, and copy number within 0.2 log of diploid is white. The samples are ordered starting with telomeric deletions, segmental telomeric gains (blue arrowhead), segmental MYC gains (black arrowhead) and centromeric deletions and/or gains.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4126852&req=5

Figure 1: Copy number abnormalities in the MYC locus in MM tumors and cell linesSegmented Agilent 244k aCGH of the MYC locus (chr8: 126000000-130000000) in 101 of 238 MM tumors and 42 of 53 MMCL with CNA viewed in IGV is shown. The overall copy number for the region for each sample has been normalized to two copies in order to highlight local changes in copy number. More then a one log gain is deep red, more then one log loss is deep blue, and copy number within 0.2 log of diploid is white. The samples are ordered starting with telomeric deletions, segmental telomeric gains (blue arrowhead), segmental MYC gains (black arrowhead) and centromeric deletions and/or gains.
Mentions: Fifty-three independent MMCL were analyzed for MYC locus rearrangements by metaphase FISH assays as described previously.10 Including two MMCL that express MYCL or MYCN, MYC rearrangements involving a MYC family member were detected in 42/53 (79%) MMCL (Table S1, Table S2). Most rearrangements were complex translocations or insertions. The 244K Agilent array CGH platform also detected MYC locus (but not MYCL or MYCN) copy number abnormalities (CNA) identifying unbalanced rearrangements in 42/53 (79%) MMCL, including five for which rearrangements were not detected by the karyotypic assays (Figure 1,Table S1, Table S2). No MYC locus rearrangements were detected by either assay in 6/53 (11%) of MMCL. Twenty-eight of the 47 MMCL with MYC rearrangements repositioned a MYC family member near one of the IG 3’ enhancer sequences that are included in the FISH probes: 21 with IGH, 5 with IGL, and 2 with IGK (Table S2). Rearrangements in the remaining 19 MMCL did not reveal recurrent partner loci.

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