3’Igh enhancers hs3b/hs4 are dispensable for Myc deregulation in mouse plasmacytomas with T(12;15) translocations

摘要

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).