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Cumulative Epigenetic Abnormalities in Host Genes with Viral and Microbial Infection during Initiation and Progression of Malignant Lymphoma/Leukemia.

Oka T, Sato H, Ouchida M, Utsunomiya A, Yoshino T - Cancers (Basel) (2011)

Bottom Line: Although cancers have been thought to be predominantly driven by acquired genetic changes, it is becoming clear that microenvironment-mediated epigenetic alterations play important roles.Tumor suppressor genes become frequent targets of aberrant hypermethylation in the course of gene-silencing due to the increased and deregulated DNA methyltransferases (DNMTs).The purpose of this article is to review the current status of knowledge about the contribution of cumulative epigenetic abnormalities of the host genes after microbial and virus infection to the crisis and progression of malignant lymphoma/leukemia.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata-cho, Okayama 700-8558, Japan. oka@md.okayama-u.ac.jp.

ABSTRACT
Although cancers have been thought to be predominantly driven by acquired genetic changes, it is becoming clear that microenvironment-mediated epigenetic alterations play important roles. Aberrant promoter hypermethylation is a prevalent phenomenon in human cancers as well as malignant lymphoma/leukemia. Tumor suppressor genes become frequent targets of aberrant hypermethylation in the course of gene-silencing due to the increased and deregulated DNA methyltransferases (DNMTs). The purpose of this article is to review the current status of knowledge about the contribution of cumulative epigenetic abnormalities of the host genes after microbial and virus infection to the crisis and progression of malignant lymphoma/leukemia. In addition, the relevance of this knowledge to malignant lymphoma/leukemia assessment, prevention and early detection will be discussed.

No MeSH data available.


Related in: MedlinePlus

Natural course from the infection of human T lymphotropic virus type-I (HTLV-I) to onset and progression of adult T-cell leukemia/lymphoma (ATLL). Accumulation of genetic and epigenetic changes in host and virus genome during long latent period induce onset of ATLL.
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f3-cancers-03-00568: Natural course from the infection of human T lymphotropic virus type-I (HTLV-I) to onset and progression of adult T-cell leukemia/lymphoma (ATLL). Accumulation of genetic and epigenetic changes in host and virus genome during long latent period induce onset of ATLL.

Mentions: ATLL is an aggressive malignant disease of CD4-positive T lymphocytes caused by infection with HTLV-I [58-60]. HTLV-I causes ATLL in 3-5% of infected individuals after a long latent period of 40–60 years [72]. Advanced acute ATLL has poor prognosis. ATLL is divided into four stages: namely, smoldering, chronic, lymphoma and acute types [73]. The smoldering and chronic types are indolent, but the acute and lymphoma types are aggressive ATLL is characterized by resistance to chemotherapy and a poor prognosis [73,74]. Such a long latent period suggests that a multi-step leukemogenic/lymphomagenic mechanism is involved in the development of ATLL, although the critical events in the progression have not been well characterized. The pathogenesis of HTLV-I has been intensively investigated in terms of the viral regulatory protein HTLV-I Tax or Rex, which is supposed to play key roles in the HTLV-I leukemogenesis/lymphomagenesis as well as the recently discovered HTLV-I basic leucine zipper factor (HBZ) [74-76]. We and others have reported the progression mechanism of ATLL from various genetic aspects, including specific chromosome abnormalities [77-82], changes of characteristic HTLV-I Tax and Rex protein expression patterns [71] and aberrant expression of the SHP1 [78,83], P53 [84,85],MELIS [85], DRS [86] and ASY/Nogo [87] genes, although the detailed mechanism triggering the onset and progression of ATLL remains to be elucidated. Frequent epigenetic aberration of DNA hypermethylation associated with the SHP1 gene silencing has been identified in a wide range of hematopoietic malignancies [83,88]. SHP1 is a nonreceptor type protein-tyrosine phosphatase, which acts as a negative regulator in hematopoietic cells. A decrease or loss of the SHP1 gene expression may be related to the malignant transformation in lymphoma and leukemia cells [72,84]. Recently, we have reported that the number of CpG island methylated genes, including the SHP1, P15, P16, P73, HCAD, DAPK and MGMT genes, increased with disease progression and that aberrant hypermethylation in specific genes was detected even in HTLV-I carriers and correlated with progression to ATLL (Figure 3)[89]. 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 with the 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 as well as the value of CpG methylation and CIMP for new diagnostic and prognostic biomarkers.


Cumulative Epigenetic Abnormalities in Host Genes with Viral and Microbial Infection during Initiation and Progression of Malignant Lymphoma/Leukemia.

Oka T, Sato H, Ouchida M, Utsunomiya A, Yoshino T - Cancers (Basel) (2011)

Natural course from the infection of human T lymphotropic virus type-I (HTLV-I) to onset and progression of adult T-cell leukemia/lymphoma (ATLL). Accumulation of genetic and epigenetic changes in host and virus genome during long latent period induce onset of ATLL.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3756377&req=5

f3-cancers-03-00568: Natural course from the infection of human T lymphotropic virus type-I (HTLV-I) to onset and progression of adult T-cell leukemia/lymphoma (ATLL). Accumulation of genetic and epigenetic changes in host and virus genome during long latent period induce onset of ATLL.
Mentions: ATLL is an aggressive malignant disease of CD4-positive T lymphocytes caused by infection with HTLV-I [58-60]. HTLV-I causes ATLL in 3-5% of infected individuals after a long latent period of 40–60 years [72]. Advanced acute ATLL has poor prognosis. ATLL is divided into four stages: namely, smoldering, chronic, lymphoma and acute types [73]. The smoldering and chronic types are indolent, but the acute and lymphoma types are aggressive ATLL is characterized by resistance to chemotherapy and a poor prognosis [73,74]. Such a long latent period suggests that a multi-step leukemogenic/lymphomagenic mechanism is involved in the development of ATLL, although the critical events in the progression have not been well characterized. The pathogenesis of HTLV-I has been intensively investigated in terms of the viral regulatory protein HTLV-I Tax or Rex, which is supposed to play key roles in the HTLV-I leukemogenesis/lymphomagenesis as well as the recently discovered HTLV-I basic leucine zipper factor (HBZ) [74-76]. We and others have reported the progression mechanism of ATLL from various genetic aspects, including specific chromosome abnormalities [77-82], changes of characteristic HTLV-I Tax and Rex protein expression patterns [71] and aberrant expression of the SHP1 [78,83], P53 [84,85],MELIS [85], DRS [86] and ASY/Nogo [87] genes, although the detailed mechanism triggering the onset and progression of ATLL remains to be elucidated. Frequent epigenetic aberration of DNA hypermethylation associated with the SHP1 gene silencing has been identified in a wide range of hematopoietic malignancies [83,88]. SHP1 is a nonreceptor type protein-tyrosine phosphatase, which acts as a negative regulator in hematopoietic cells. A decrease or loss of the SHP1 gene expression may be related to the malignant transformation in lymphoma and leukemia cells [72,84]. Recently, we have reported that the number of CpG island methylated genes, including the SHP1, P15, P16, P73, HCAD, DAPK and MGMT genes, increased with disease progression and that aberrant hypermethylation in specific genes was detected even in HTLV-I carriers and correlated with progression to ATLL (Figure 3)[89]. 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 with the 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 as well as the value of CpG methylation and CIMP for new diagnostic and prognostic biomarkers.

Bottom Line: Although cancers have been thought to be predominantly driven by acquired genetic changes, it is becoming clear that microenvironment-mediated epigenetic alterations play important roles.Tumor suppressor genes become frequent targets of aberrant hypermethylation in the course of gene-silencing due to the increased and deregulated DNA methyltransferases (DNMTs).The purpose of this article is to review the current status of knowledge about the contribution of cumulative epigenetic abnormalities of the host genes after microbial and virus infection to the crisis and progression of malignant lymphoma/leukemia.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata-cho, Okayama 700-8558, Japan. oka@md.okayama-u.ac.jp.

ABSTRACT
Although cancers have been thought to be predominantly driven by acquired genetic changes, it is becoming clear that microenvironment-mediated epigenetic alterations play important roles. Aberrant promoter hypermethylation is a prevalent phenomenon in human cancers as well as malignant lymphoma/leukemia. Tumor suppressor genes become frequent targets of aberrant hypermethylation in the course of gene-silencing due to the increased and deregulated DNA methyltransferases (DNMTs). The purpose of this article is to review the current status of knowledge about the contribution of cumulative epigenetic abnormalities of the host genes after microbial and virus infection to the crisis and progression of malignant lymphoma/leukemia. In addition, the relevance of this knowledge to malignant lymphoma/leukemia assessment, prevention and early detection will be discussed.

No MeSH data available.


Related in: MedlinePlus