3’Ighenhancers hs3b/hs4 are dispensable forMycderegulation in mouse plasmacytomas with T(12;15) translocations

Abstract

Myc-deregulating T(12;15) chromosomal translocations are the hallmark cytogenetic abnormalities of murine plasmacytomas (PCTs). In most PCTs, the immunoglobulin heavy chain (Igh) locus is broken between the Eμ enhancer and the 3’ regulatory region (3’RR), making the latter the major candidate for orchestrating Myc deregulation. To elucidate the role of the Igh3’RR in tumorigenesis, we induced PCTs in Bcl-xL-transgenic mice deficient for the major Igh3’RR enhancer elements, hs3b and hs4 (hs3b-4-/-). Contrary to previous observations using a mouse lymphoma model, which showed no tumors with peripheral B-cell phenotype in hs3b-4-/- mice, these animals developed T(12;15)-positive PCTs, although with a lower incidence than hs3b-4+/+ (wild-type, WT) controls. In heterozygous hs3b-4+/- mice there was no allelic bias in targeting Igh for T(12;15). Molecular analyses of Igh/Myc junctions revealed dominance of Sμ region breakpoints versus the prevalence of Sγ or Sα in WT controls. Myc expression and Ig secretion in hs3b-4-/- PCTs did not differ from WT controls. We also evaluated the effect of a complete Igh3’RR deletion on Myc expression in the context of an established Igh/Myc translocation in ARS/Igh11-transgenic PCT cell lines. Cre-mediated deletion of the Igh3’RR resulted in gradual reduction of Myc expression, loss of proliferative activity and increased cell death, confirming the necessity of the Igh3’RR for Myc deregulation by T(12;15).

Eμ and 3′RR transcriptional enhancers of the IgH locus cooperate to promote c-myc–induced mature B-cell lymphomas

“…7 39RR knock-out models indicate that its deletion affects mature B-cell lymphoma occurrence, highlighting the key role of this IgH cis-regulatory region for lymphoma progression. 34,35,45 Therefore, as previously reported by us and others, 3,35,46 39RR targeting would in theory provide a potential strategy for the treatment of mature B-cell lymphomas. Translocations in B-cell lymphomas induce epigenetic changes, 47 suggesting that epigenetic drugs that target histone acetylation (inhibitors of histone deacetylases) and histone methylation (EZH2 inhibitors) may provide a new strategy to treat several B-cell lymphoid malignancies.…”

“…At this time, the development of c-myc-induced plasmacytomas in mice bearing a truncated 39RR gave divergent results. 34,35 Insertion of c-myc into the IgH locus displayed an increase in c-myc transcripts in B cells of young mice. In most cell types, c-myc enforces proliferation but also triggers apoptosis.…”

Mouse Models of c-myc Deregulation Driven by IgH Locus Enhancers as Models of B-Cell Lymphomagenesis

“…In contrast, 3'RR integrity (for its optimal transcriptional activity) is required for B-cell lymphomas with CSR-associated translocations (57). In another study modeling murine plasmacytomas with T (12,15) translocations, the same hs3b-hs4 deletion of the 3'RR in Bcl-xL transgenic mice was without effect for Myc deregulation and mouse plasmacytoma generation (58). However, total 3'RR deletion in these plasmacytomas lowered Myc expression and cell growth confirming 3'RR involvement for myc deregulation by T (12,15…”

Enhancing B-Cell Malignancies—On Repurposing Enhancer Activity towards Cancer

“…Which of them are of key importance for translocated oncogene expression? Kovalchuk et al showed that hs3a and hs1,2 enhancers are important drivers of Myc overexpression in mouse plasmacytomas, while hs3b and hs4 are dispensable [204]. Another study indicated that 3 RR is not obligatory for translocated c-Myc expression in pro-B cell lymphomas, but essential in peripheral B-cell lymphomas [205].…”