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Loss of H19 imprinting in adult T‐cell leukaemia/lymphoma

2007; Wiley; Volume: 137; Issue: 4 Linguagem: Inglês

10.1111/j.1365-2141.2007.06581.x

1365-2141

Seisho Takeuchi, Wolf‐Karsten Hofmann, Kunihiro Tsukasaki, Naoko Takeuchi, Takayuki Ikezoe, Masahide Matsushita, Yoshio Uehara, H. Phillip Koeffler,

T-cell and Retrovirus Studies

Adult T-cell leukaemia/lymphoma (ATL) is associated with the monoclonal integration of human T-lymphotropic virus type I (HTLV-I) proviral DNA into tumour cells, but the incidence of ATL is low (2–5%) among HTLV-I carriers; and those who develop the disease usually have a 40- to 60-year latency period from the time of infection to progression to ATL. These phenomena suggest that additional mechanisms are involved in the progress of the disease, such as inactivation of tumour suppressor genes, or activation of oncogenes. Genomic imprinting is an epigenetic alteration in DNA. Loss of imprinting (LOI) results in loss of parental origin-specific differential allele expression, and leads to activation of the normally silent copy of the gene. H19 is an endogenous gene showing maternal-specific monoallelic expression on 11p15. Previous studies have found that loss of H19 imprinting is associated with development of several kinds of cancers (Hashimoto et al, 1995; Hibi et al, 1996). Twenty ATL patients were diagnosed at the Department of Haematology, Nagasaki University School of Medicine. Bone marrow cells from nine patients with acute lymphoblastic leukaemia (ALL) were obtained from the German multicentre ALL Study Group. ATL cell lines KK1, SO4 and ST1 were kindly provided by Dr K. Tsukasaki (Nagasaki University School of Medicine, Japan). The presence of a polymorphic pattern and gene expression pattern of H19 were examined in each case using RsaI restriction fragment length polymorphic (RFLP) analysis as described previously (Hibi et al, 1996). Seven primary ALL samples, 11 ATL samples and two ATL cell lines were heterozygous for the RsaI polymorphism in H19 (Fig 1). These heterozygous samples were interpreted as informative cases that can be used in allele-specific expression analysis. The heterozygous samples in expression analysis were interpreted as having LOI. Seven of 11 (64%) informative ATL samples and two of two (100%) informative ATL cell lines showed LOI for H19 (Fig 1). LOI was found in three of four (75%) chronic ATL patients, and in four of seven (57%) acute ATL patients. In contrast, six of seven (86%) informative primary ALL samples did not have LOI. Loss of imprinting (LOI) of the H19 gene in adult T-cell leukaemia/lymphoma. Case 1 showed LOI. Case 4 displayed maintenance of imprinting. Both cases 3 and 6 were not informative for the RsaI polymorphism. Polymerase chain reaction products (655 bp) with the RsaI site were digested into 485 and 170 bp fragments. Reverse transcription polymerase chain reaction products (575 bp) with the RsaI site were digested into 405 and 170 bp fragments. We have found that LOI of H19 is a frequent event in ATL. H19 encodes a polyadenylated RNA that lacks conserved open reading frames. No endogenous translation product has been identified; therefore, it was proposed that H19 RNA functions as a riboregulator. A recent study has found that H19 is activated by the E2F1 transcription factor, and overexpression of H19 confers a growth advantage in breast cancer cells (Berteaux et al, 2005). Moreover, the c-Myc oncogene induces the expression of H19 RNA (Barsyte-Lovejoy et al, 2006). Therefore, H19 may have an important role in transformation of many kinds of tumours. LOI of H19 was initially found in childhood tumours, including Wilms tumour (Rainier et al, 1995), hepatoblastoma, testicular germ cell tumour and choriocarcinoma (Hashimoto et al, 1995). It was later identified in adult tumours. These include oesophageal cancer (Hibi et al, 1996) and lung cancer. On the other hand, maintenance of imprinting has been identified in neuroblastoma, glioma and colorectal cancer (Hibi et al, 1996). These findings indicate that LOI of H19 is involved in several types of tumour. A previous study showed that H19 imprinting was maintained in both immature and mature haematopoietic cells (Morison et al, 2000); therefore, LOI identified in the current study, is not due to the immature phenotype of the affected cells. LOI was identified both in chronic and in acute ATL, indicating that it is associated with the initiation rather than the progression of ATL. Supported in part by grants from National Institutes of Health, Honara Shapiro Fund, Parker Hughes Trust, Sheryl and David Weisberg Foundation, Grant-in-Aid from the Ministry of Education, Culture Sports, Science and Technology of Japan. H. P. K. is a member of the Jonsson Comprehensive Cancer Center and Molecular Biology Institute of UCLA, and holds the endowed Mark Goodson Chair of Oncology Research at Cedars-Sinai Medical Center/UCLA School of Medicine.