Alteration of enhancer of polycomb 1 at 10p11.2 is one of the genetic events leading to development of adult T‐cell leukemia/lymphoma

Abstract

Adult T-cell leukemia/lymphoma (ATLL) is a malignant tumor caused by latent human T-lymphotropic virus 1 (HTLV-1) infection. We previously identified a common breakpoint cluster region at 10p11.2 in acute-type ATLL by spectral karyotyping. Single nucleotide polymorphism array comparative genomic hybridization analysis of the breakpoint region in three ATLL-related cell lines and four patient samples revealed that the chromosomal breakpoints are localized within the enhancer of polycomb 1 (EPC1) gene locus in an ATLL-derived cell line (SO4) and in one patient with acute-type ATLL. EPC1 is a human homologue of the E(Pc) enhancer of polycomb gene of Drosophila. Inappropriate expression of the polycomb group gene family has been linked to the loss of normal gene silencing pathways, which can contribute to the loss of cell identity and malignant transformation in many kinds of cancers. In the case of the SO4 cell line, which carried a der(10)t(2;10)(p23;p11.2) translocation, EPC1 was fused with the additional sex combs-like 2 (ASXL2) gene at 2p23.3 (EPC1/ASXL2). In the case with an acute-type ATLL, who carried a der(10)del(10)(p11.2)del(10)(q22q24) translocation, a putative truncated EPC1 gene (EPC1tr) was identified. Overexpression of EPC1/ASXL2 enhanced cell growth in T-leukemia cells, and a GAL4-EPC1/ASXL2 fusion protein showed high transcriptional activity. Although a GAL4-EPC1tr fusion protein did not activate transcription, overexpression of EPC1tr accelerated cell growth in leukemia cells, suggesting that the EPC1 structural abnormalities in the SO4 cell line and in the patient with acute-type ATLL may contribute to leukemogenesis.

Human Genetic Determinants of Viral Diseases

“…A genome-wide linkage analysis mapped a major susceptibility locus for predisposition to HTLV-1 infection in African breastfed children to chromosome 6q27 (119), though the causative locus has not been determined. Recently, spectral karyotyping in patients with aggressive type ATL—characterized by less than 10 months survival—identified a common breakpoint cluster region on chromosome 10 (106). The chromosomal breakpoints clustered within the EPC1 gene locus, which codes for a protein involved in histone acetylation and gene transcriptional regulation.…”

“…The chromosomal breakpoints clustered within the EPC1 gene locus, which codes for a protein involved in histone acetylation and gene transcriptional regulation. Overexpression of EPC1 accelerated leukemia cell growth in vitro, suggesting that altered levels of EPC1 may contribute to leukemogenesis in patients with aggressive-type ATL (106). …”

High-throughput transcription profiling identifies putative epigenetic regulators of hematopoiesis

“…Although the specific functions of CBX8 and EPC1 in hematopoiesis or in leukemia have not been fully characterized, CBX8 has been shown to be essential for MLL-AF9-induced AML, 50 and EPC1 has been shown to be involved in chromosomal translocation in ALL. 51 MLL5, PDRM2, and DNMT1 have been reported to be deregulated in cancer. MLL5 and PDRM2 are potential tumor suppressor genes, whereas DNMT1 is known to methylate CpG islands in tumor suppressor gene promoters.…”

Human T-cell Lymphotropic Virus Type I–Associated Adult T-cell Leukemia–Lymphoma: New Directions in Clinical Research

“…However, the expression of Tax, which is very immunogenic, should be transient on each HTLV-1-infected cell escaping the immune surveillance of the host. Thereafter HTLV-1-infected cells can transform with a combination of the continued expression of HBZ, acquired epigenetic regulation of cell-transforming factors, full-blown development of ATL with the genetic/epigenetic loss of function of tumor suppressor genes and microRNAs (miRNA), and activation of oncogenes (12,23,24,(27)(28)(29)(30)(31)(32)(33)(34). These abnormalities are acquired during the progression of ATL from the indolent to the aggressive subtypes.…”