Promiscuous Structural Variants Drive Myeloma Initiation and Progression

Abstract

A comprehensive genomic analysis of structural variants in multiple myeloma in this issue highlights the key role of these events, involving primarily the immunoglobulin heavy chain locus in disease initiation and the MYC locus in disease progression. However, the current study reveals the large number of genomic hotspots, oncogenes, tumor suppressor genes, and recombination mechanisms that contribute to multiple myeloma heterogeneity. See related article by Rustad et al., p. 258.

Figure 1.

A, Model for possible resolutions of a double-strand break with duplicated sequences. A double strand break (1), with generation of duplicated sequences “cdef” on both sides of the breakpoint (2), can be repaired with generation of tandem duplicated sequence (3), insertion of an unrelated piece of DNA (4), and reciprocal translocation without (5) or with duplication “UVWX” on the partner chromosome (6). B, Insertion of an 11;14 fragment containing 3′ IGH enhancer (3′E) 11q13 breakpoint, but not CCND1 gene, in the KMS12 multiple myeloma cell line. C, Insertion of an 11;14 fragment containing the 3′ IGH enhancer 11q13 breakpoint, but not CCND1 gene, and also a chromosome 8 fragment containing the MYC gene between duplicated sequences on chromosome 4. For B and C, chromosome 8 is blue, chromosome 14 is green, chromosome 11 is orange, and chromosome 4 is red with duplicated sequences underlined and a possible super-enhancer (SE) indicated.