Evidence of an epigenetic origin for high-risk 1q21 copy number aberrations in multiple myeloma

• Published in: Blood Vol. 125; no. 24; pp. 3756 - 3759
• Main Authors: Sawyer, Jeffrey R., Tian, Erming, Heuck, Christoph J., Johann, Donald J., Epstein, Joshua, Swanson, Charles M., Lukacs, Janet L., Binz, Regina Lichti, Johnson, Marian, Sammartino, Gael, Zangari, Maurizio, Davies, Faith E., van Rhee, Frits, Morgan, Gareth J., Barlogie, Bart
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 11.06.2015; American Society of Hematology
• Subjects: Brief Report; Chromosome Aberrations; Chromosomes, Human, Pair 1 - genetics; DNA Methylation; Epigenesis, Genetic; Gene Dosage; Humans; Lymphoid Neoplasia; Multiple Myeloma - genetics; Translocation, Genetic
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2015-03-632075

Multiple myeloma is a B-cell malignancy stratified in part by cytogenetic abnormalities, including the high-risk copy number aberrations (CNAs) of +1q21 and 17p−. To investigate the relationship between 1q21 CNAs and DNA hypomethylation of the 1q12 pericentromeric heterochromatin, we treated in vitro peripheral blood cultures of 5 patients with balanced constitutional rearrangements of 1q12 and 5 controls with the hypomethylating agent 5-azacytidine. Using G-banding, fluorescence in situ hybridization, and spectral karyotyping, we identified structural aberrations and copy number gains of 1q21 in the treated cells similar to those found in patients with cytogenetically defined high-risk disease. Aberrations included 1q12 triradials, amplifications of regions juxtaposed to 1q12, and jumping translocations 1q12. Strikingly, all 5 patients with constitutional 1q12 rearrangements showed amplifications on the derivative chromosomes distal to the inverted or translocated 1q12 region, including MYCN in 1 case. At the same time, no amplification of the 1q21 region was found when the 1q12 region was inverted or absent. These findings provide evidence that the hypomethylation of the 1q12 region can potentially amplify any genomic region juxtaposed to it and mimic CNAs found in the bone marrow of patients with high-risk disease. •High-risk copy number gains of 1q21 originate in part by the hypomethylation of 1q12 pericentromeric heterochromatin.•Novel CNAs can result from juxtaposition of chromosomal regions to hypomethylated 1q12.