Multi-Step Aberrant CpG Island Hyper-Methylation Is Associated with the Progression of Adult T–Cell Leukemia/Lymphoma

Abstract

Aberrant CpG island methylation contributes to the pathogenesis of various malignancies. However, little is known about the association of epigenetic abnormalities with multistep tumorigenic events in adult T cell leukemia/lymphoma (ATLL). To determine whether epigenetic abnormalities induce the progression of ATLL , we analyzed the methylation profiles of the SHP1 , p15 , p16 , p73 , HCAD, DAPK , hMLH-1, and MGMT genes by methylation specific PCR assay in 65 cases with ATLL patients. The number of CpG island methylated genes increased with disease progression and aberrant hypermethylation in specific genes was detected even in HTLV-1 carriers and correlated with progression to ATLL. The CpG island methylator phenotype (CIMP) was observed most frequently in lymphoma type ATLL and was also closely associated with the progression and crisis of ATLL. The high number of methylated genes and increase of CIMP incidence were shown to be unfavorable prognostic factors and correlated with a shorter overall survival by Kaplan-Meyer analysis. The present findings strongly suggest that the multistep accumulation of aberrant CpG methylation in specific target genes and the presence of CIMP are deeply involved in the crisis , progression , and prognosis of ATLL , as well as indicate the value of CpG methylation and CIMP for new diagnostic and prognostic biomarkers.

Constitutive activation of STAT3 in Sézary syndrome is independent of SHP-1

“…25 In normal cells, the JAK-STAT3 pathway is tightly regulated, primarily by negative feedback mechanisms involving the protein inhibitors of activated STATs, the suppressors of cytokine signalling (SOCS) and the SH2-containing phosphatases (SHPs). Loss of SHP-1 expression has been linked to aberrant JAK-STAT3 activation in several malignancies, including multiple myeloma, 26 adult T-cell leukaemia/lymphoma 27 and in a subset of MF patients with large cell transformation 28,29 or advanced tumour stage disease. 30 The mechanism of SHP-1 inactivation has been attributed to epigenetic silencing by aberrant promoter hypermethylation, demonstrated by methylation-specific PCR (MSP) in CTCL-derived cell lines, 28 and in diagnostic samples from myeloma 26 and adult T-cell leukaemia/ lymphoma 27 rather than due to inactivating mutations.…”

Accumulation of Specific Epigenetic Abnormalities During Development and Progression of T Cell Leukemia/Lymphoma

“…Frequent epigenetic aberration of DNA hypermethylation associated with SHP1 gene silencing has been identified in a wide range of hematopoietic malignancies (Oka et al, 2001(Oka et al, , 2002Koyama et al, 2003). Recently, the number of genes methylated CpG islands, including the SHP1, P15, P16, P73, HCAD, DAPK, and MGMT genes, has been reported to increase with disease progression, and aberrant hypermethylation in specific genes has been detected even in HTLV-1 carriers, and correlated with eventual progression to ATLL (Sato et al, 2010). CIMP was observed most frequently in the lymphoma type ATLL, and was also closely associated with the progression and crisis of ATLL.…”

“…In particular, the sIL-2R level has been considered to be an indicator of disease progression and prognosis (Kamihira et al, 1994). Multi-step aberrant CpG island hyper-methylation was detected in ATLL patients, which was associated with the progression and transformation (crisis) of ATLL (Sato et al, 2010). Clonal evolution of ATLL cells often occurs at the time of acute transformation in ATLL patients.…”

“…CIMP was observed most frequently in the lymphoma type ATLL, and was also closely associated with the progression and crisis of ATLL. The high number of methylated genes, and the increased incidence of CIMP were shown to be unfavorable prognostic factors for ATLL (Sato et al, 2010) and correlated with a shorter overall survival as calculated by a Kaplan-Meyer analysis. These findings strongly suggest that the multi-step accumulation of aberrant CpG methylation in specific target genes and the presence of CIMP are deeply involved in the crisis, progression and prognosis of ATLL, and that CpG methylation and CIMP may provide new diagnostic and prognostic biomarkers for patients with this disease (Figure 2).…”

New developments in the pathology of malignant lymphoma: a review of the literature published from October 2009 to January 2010

“…Sato et al [65] could positively correlate increased CpG island methylation with progression in 65 patients with adult T-cell leukemia/lymphoma.…”