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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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Dysregulation of MYC causes the progression of MGUS to MMA. Wild type C57Bl/6, but not Balb/c, mice develop faint (<4g/L), non-progressive M-spikes detectable by serum protein electrophoresis, with a median Time To Spike (TTS) detection of 97 weeks (left panel). With the introduction of the Vk*MYC transgene, C57Bl/6 mice develop progressively increasing M-spikes with a median Time To Spike >7g/L of 67 weeks. In contrast wild type C57Bl/6 or Vk*MYC Balb/c mice rarely develop an M-spike >7g/L, and it is never progressive (middle panel). Representative serum protein electrophoresis is shown for Vk*MYC C56BL/6 and Vk*MYC Balb/c mice (right panel).B. Proposed model summarizing the role of MYC in the progression of MM. The height of the boxed region indicates the fraction of tumors with MYC rearrangements at different stages. MGUS: white, low MYC expression. MM: light gray, increased MYC expression without a MYC rearrangement; dark gray, substantially increased MYC expression with a MYC rearrangement; intermediate gray, unknown. Increased MYC expression is due to unknown trans- mechanisms that result in bi-allelic expression in at least 50% of early MM tumors. Mono-allelic expression as a result of a MYC locus rearrangement might occur with this transition in some (? ~15%) MM tumors. Most MYC rearrangements probably occur during progression of MM, with >50% in advanced MM and 90% in MMCL.
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Figure 5: Dysregulation of MYC causes the progression of MGUS to MMA. Wild type C57Bl/6, but not Balb/c, mice develop faint (<4g/L), non-progressive M-spikes detectable by serum protein electrophoresis, with a median Time To Spike (TTS) detection of 97 weeks (left panel). With the introduction of the Vk*MYC transgene, C57Bl/6 mice develop progressively increasing M-spikes with a median Time To Spike >7g/L of 67 weeks. In contrast wild type C57Bl/6 or Vk*MYC Balb/c mice rarely develop an M-spike >7g/L, and it is never progressive (middle panel). Representative serum protein electrophoresis is shown for Vk*MYC C56BL/6 and Vk*MYC Balb/c mice (right panel).B. Proposed model summarizing the role of MYC in the progression of MM. The height of the boxed region indicates the fraction of tumors with MYC rearrangements at different stages. MGUS: white, low MYC expression. MM: light gray, increased MYC expression without a MYC rearrangement; dark gray, substantially increased MYC expression with a MYC rearrangement; intermediate gray, unknown. Increased MYC expression is due to unknown trans- mechanisms that result in bi-allelic expression in at least 50% of early MM tumors. Mono-allelic expression as a result of a MYC locus rearrangement might occur with this transition in some (? ~15%) MM tumors. Most MYC rearrangements probably occur during progression of MM, with >50% in advanced MM and 90% in MMCL.

Mentions: Increasingly, it has become apparent that dysregulation of MYC (less often MYCN or MYCL) is an essential event in MM.19, 51-53. Previous results indicated that germinal center activation of a MYC transgene caused progression of MGUS to MM in an MGUS prone mouse strain, a conclusion that is supported by new results showing that the same transgene does not cause MM in a mouse strain that rarely develops MGUS (Figure 5A). The increased MYC expression at the MGUS/MM transition can be bi-allelic, or mono-allelic if there is a MYC rearrangement. Given the evidence for heterogeneity of MYC rearrangements in about 15% of treated or untreated MM tumors with MYC:IGH or MYC: IGL rearrangements, it is clear that the prevalence of MYC rearrangements increases during tumor progression.10, 12, 54 Initially, we had proposed that most MYC rearrangements were a late progression event. However, in view of a high and similar prevalence of MYC rearrangements in untreated and treated MM tumors, and in SMM tumors, it now seems possible that some of these rearrangements occur early (Figure 5B). One caveat is that the MMRC tumors analyzed may be skewed towards more advanced stages of disease (Methods and Table S14).


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)

Dysregulation of MYC causes the progression of MGUS to MMA. Wild type C57Bl/6, but not Balb/c, mice develop faint (<4g/L), non-progressive M-spikes detectable by serum protein electrophoresis, with a median Time To Spike (TTS) detection of 97 weeks (left panel). With the introduction of the Vk*MYC transgene, C57Bl/6 mice develop progressively increasing M-spikes with a median Time To Spike >7g/L of 67 weeks. In contrast wild type C57Bl/6 or Vk*MYC Balb/c mice rarely develop an M-spike >7g/L, and it is never progressive (middle panel). Representative serum protein electrophoresis is shown for Vk*MYC C56BL/6 and Vk*MYC Balb/c mice (right panel).B. Proposed model summarizing the role of MYC in the progression of MM. The height of the boxed region indicates the fraction of tumors with MYC rearrangements at different stages. MGUS: white, low MYC expression. MM: light gray, increased MYC expression without a MYC rearrangement; dark gray, substantially increased MYC expression with a MYC rearrangement; intermediate gray, unknown. Increased MYC expression is due to unknown trans- mechanisms that result in bi-allelic expression in at least 50% of early MM tumors. Mono-allelic expression as a result of a MYC locus rearrangement might occur with this transition in some (? ~15%) MM tumors. Most MYC rearrangements probably occur during progression of MM, with >50% in advanced MM and 90% in MMCL.
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Related In: Results  -  Collection

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Figure 5: Dysregulation of MYC causes the progression of MGUS to MMA. Wild type C57Bl/6, but not Balb/c, mice develop faint (<4g/L), non-progressive M-spikes detectable by serum protein electrophoresis, with a median Time To Spike (TTS) detection of 97 weeks (left panel). With the introduction of the Vk*MYC transgene, C57Bl/6 mice develop progressively increasing M-spikes with a median Time To Spike >7g/L of 67 weeks. In contrast wild type C57Bl/6 or Vk*MYC Balb/c mice rarely develop an M-spike >7g/L, and it is never progressive (middle panel). Representative serum protein electrophoresis is shown for Vk*MYC C56BL/6 and Vk*MYC Balb/c mice (right panel).B. Proposed model summarizing the role of MYC in the progression of MM. The height of the boxed region indicates the fraction of tumors with MYC rearrangements at different stages. MGUS: white, low MYC expression. MM: light gray, increased MYC expression without a MYC rearrangement; dark gray, substantially increased MYC expression with a MYC rearrangement; intermediate gray, unknown. Increased MYC expression is due to unknown trans- mechanisms that result in bi-allelic expression in at least 50% of early MM tumors. Mono-allelic expression as a result of a MYC locus rearrangement might occur with this transition in some (? ~15%) MM tumors. Most MYC rearrangements probably occur during progression of MM, with >50% in advanced MM and 90% in MMCL.
Mentions: Increasingly, it has become apparent that dysregulation of MYC (less often MYCN or MYCL) is an essential event in MM.19, 51-53. Previous results indicated that germinal center activation of a MYC transgene caused progression of MGUS to MM in an MGUS prone mouse strain, a conclusion that is supported by new results showing that the same transgene does not cause MM in a mouse strain that rarely develops MGUS (Figure 5A). The increased MYC expression at the MGUS/MM transition can be bi-allelic, or mono-allelic if there is a MYC rearrangement. Given the evidence for heterogeneity of MYC rearrangements in about 15% of treated or untreated MM tumors with MYC:IGH or MYC: IGL rearrangements, it is clear that the prevalence of MYC rearrangements increases during tumor progression.10, 12, 54 Initially, we had proposed that most MYC rearrangements were a late progression event. However, in view of a high and similar prevalence of MYC rearrangements in untreated and treated MM tumors, and in SMM tumors, it now seems possible that some of these rearrangements occur early (Figure 5B). One caveat is that the MMRC tumors analyzed may be skewed towards more advanced stages of disease (Methods and Table S14).

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