1q12 chromosome translocations form aberrant heterochromatic foci associated with changes in nuclear architecture and gene expression in B cell lymphoma

Abstract

Epigenetic perturbations are increasingly described in cancer cells where they are thought to contribute to deregulated gene expression and genome instability. Here, we report the first evidence that a distinct category of chromosomal translocations observed in human tumours—those targeting 1q12 satellite DNA—can directly mediate such perturbations by promoting the formation of aberrant heterochromatic foci (aHCF). By detailed investigations of a 1q12 translocation to chromosome 2p, in a case of human B cell lymphoma, aberrant aHCF were shown to be localized to the nuclear periphery and to arise as a consequence of long range ‘pairing’ between the translocated 1q12 and chromosome 2 centromeric regions. Remarkably, adjacent 2p sequences showed increased levels of repressive histone modifications, including H4K20me3 and H3K9me3, and were bound by HP1. aHCF were associated to aberrant spatial localization and deregulated expression of a novel 2p gene (GMCL1) that was found to have prognostic impact in diffuse large B cell lymphoma. Thus constitutive heterochromatin rearrangements can contribute to tumourigenesis by perturbing gene expression via long range epigenetic mechanisms.

Jumping translocations of 1q12 in multiple myeloma: a novel mechanism for deletion of 17p in cytogenetically defined high-risk disease

“…For example, in patient 17, we identified the focal amplification of 16q11 translocated to 18q as part of a second translocation of the same JT1q12 ( Figure 2A). The der (20) in this cell line did not show a signal for 16q11 and, therefore, was not a sequential JT1q12 (Figure 2A). In a second more complex example, patient 59, 2 sequential specimens were analyzed.…”

“…32 We and others have previously speculated that the cause of these duplications and jumping translocations of 1q may be region-specific hypomethylation of the 1q12 pericentromeric heterochromatin. [18][19][20][21][22] The 1q12 pericentromeric region is a distinctive region in the human genome in that it is the largest single block of late-replicating, highly repetitive satII/III DNA that is known to contain unstable segmental duplications (low copy repeats). It is thought that a 5-azacytidine fragile site at 1q12 may play a role in the incomplete replication (delayed condensation), breaks, and triradial configurations of 1q12.…”

“…17 The primary mechanism for amplification of 1q21 in MM is the whole-arm CN aberration known as the jumping translocation 1q (JT1q12). [18][19][20][21] A JT1q12 occurs when a duplication of the 1q12 pericentromeric region translocates (jumps) as a donor chromosome (DC) segment to one or more receptor chromosomes (RCs). In most cases, JT1q12 becomes a stable clonal aberration; however, the JT1q12 can also translocate to a second RC or, alternatively, "jump off" a RC and be lost from the cell in the form of a single or multiple micronuclei.…”

Haploinsufficiency for NR3C1, the gene encoding the glucocorticoid receptor, in blastic plasmacytoid dendritic cell neoplasms

“…23 Cytogenetics, FISH, molecular analyses, and aCGH R-banded karyotyping, fluorescence in situ hybridization (FISH) analyses, and array comparative genomic hybridization (aCGH) were performed by standard methods, as previously described. 10,25 All cytogenetic and aCGH data were centrally reviewed by the Groupe Francophone de Cytogénétique Hématologique and the French BPDCN network. Karyotypes were described according to the International System for Human Cytogenetic Nomenclature.…”

“…Chromatin immunoprecipitation (ChIP) experiments were performed as described by Fournier et al 25 (native chromatin) or using the Magna ChIP kit (Millipore; cross-linked chromatin), following the manufacturer's instructions. Briefly, all ChIP assays were performed in triplicate in at least 2 independent chromatin preparations.…”