Cooperativity of imprinted genes inactivated by acquired chromosome 20q deletions

Abstract

Large regions of recurrent genomic loss are common in cancers; however, with a few well-characterized exceptions, how they contribute to tumor pathogenesis remains largely obscure. Here we identified primaterestricted imprinting of a gene cluster on chromosome 20 in the region commonly deleted in chronic myeloid malignancies. We showed that a single heterozygous 20q deletion consistently resulted in the complete loss of expression of the imprinted genes L3MBTL1 and SGK2, indicative of a pathogenetic role for loss of the active paternally inherited locus. Concomitant loss of both L3MBTL1 and SGK2 dysregulated erythropoiesis and megakaryopoiesis, 2 lineages commonly affected in chronic myeloid malignancies, with distinct consequences in each lineage. We demonstrated that L3MBTL1 and SGK2 collaborated in the transcriptional regulation of MYC by influencing different aspects of chromatin structure. L3MBTL1 is known to regulate nucleosomal compaction, and we here showed that SGK2 inactivated BRG1, a key ATP-dependent helicase within the SWI/ SNF complex that regulates nucleosomal positioning. These results demonstrate a link between an imprinted gene cluster and malignancy, reveal a new pathogenetic mechanism associated with acquired regions of genomic loss, and underline the complex molecular and cellular consequences of "simple" cancer-associated chromosome deletions.

Germline and somatic imprinting in the nonhuman primate highlights species differences in oocyte methylation

“…Our macaque data show conserved L3MBTL1 imprinting between primate species and also expand the present understanding of tissue-specific imprinting at this locus, which is not imprinted in mouse or marsupial (Aziz et al 2013).…”

“…Previously, we determined that the primate-specific imprinted gene, L3MBTL1, associates with a maternal germline imprint (Aziz et al 2013). In this study, all eight DMRs showed germline methylation consistent with the expected parental origin of the locus (Fig.…”

“…1). SGK2, located immediately downstream from L3MBTL1, is polymorphically imprinted in macaque, suggesting that it could be imprinted as a bystander to the regulation at L3MBTL1 (Aziz et al 2013). Intriguingly, we also noted that imprinted expression of L3MBTL1 and SGK2 in adult macaque .…”

Array comparative genomic hybridization and sequencing of 23 genes in 80 patients with myelofibrosis at chronic or acute phase

“…Genes included in the del(20q), such as L3MBTL1, have been studied for their possible involvement in leukemogenesis. However, sequencing analyses of 20q genes did not detect any mutation, 43 suggesting that haploinsufficiency of several genes of this chromosomal region could contribute to leukemogenesis. We compared the two minimal CDRs we identified with other studies (Online Supplementary Figure S6).…”

Mosaic chromosome 20q deletions are more frequent in the aging population

“…[10][11][12][13] It is hypothesized that haploinsufficiency of one or more tumor suppressors in a cluster of imprinted genes in the MDR could lead to a loss of expression, which may contribute to myeloid disorder development. [14][15][16] Mapping studies have focused on two such candidate tumor suppressors: L3MBTL1 and SGK2. Repression of L3MBTL1 has been shown to increase MYC expression in cell lines and could cooperate with SGK2, a regulator of the SWItch/sucrose nonfermentable-like chromatin-remodeling complex, in the epigenetic regulation of MYC expression.…”