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

The genetic abnormalities found in various types of leukemia and lymphoma do not provide a complete picture of the molecular mechanism(s) responsible for hematopoietic malignancies. Aberrant changes in epigenetics, including systems controlling DNA methylation, histone modifications, chromatin remodeling and miRNAs, are additional mechanisms that contribute to the malignant phenotype. DNA methylation is one of the basic mechanisms that controls the development and differentiation, and maintains the normal physiological status, in mammalian cells. DNA methylation is also involved in the regulation of imprinted gene expression and X-chromosome inactivation, and in the finetuning of tissue specific differentiation and development from stem cells. However, aberrant promoter hypermethylation of CpG islands leads to epigenetic silencing of multiple genes, including tumor suppressor genes, and has been recognized as an important mechanism involved in carcinogenesis. Furthermore, multiple genes have been shown to be methylated simultaneously (a condition termed the CpG island methylator phenotype: CIMP) in various types of human malignancies. This mechanism is a fundamental process involved in the development of many tumors. A comprehensive knowledge of the methylation profile of a given tumor may provide important information for risk assessment, diagnosis, monitoring, and treatments. Adult T cell leukemia/lymphoma (ATLL) is an aggressive malignant disease of CD4positive T lymphocytes caused by infection with human T-lymphotropic virus type I (HTLV-1). HTLV-1 causes ATLL in 3-5% of infected individuals after a long latent period of 40-60 years. Such a long latent period suggests that a multi-step leukemogenic/lymphomagenic mechanism is involved in the development of ATLL, although the critical event(s) involved in the progression have not been characterized in details. The pathogenesis of HTLV-1 has been investigated intensively in terms of the viral regulatory proteins HTLV-1 Tax and Rex, which are supposed to play key roles in the HTLV-1 leukemogenesis/lymphomagenesis, as well as the HTLV-1 basic leucine zipper factor (HBZ). The mechanism(s) underlying the progression of ATLL have been reported from various genetic aspects, including specific chromosome abnormalities and changes in


Introduction
The genetic abnormalities found in various types of leukemia and lymphoma do not provide a complete picture of the molecular mechanism(s) responsible for hematopoietic malignancies.Aberrant changes in epigenetics, including systems controlling DNA methylation, histone modifications, chromatin remodeling and miRNAs, are additional mechanisms that contribute to the malignant phenotype.DNA methylation is one of the basic mechanisms that controls the development and differentiation, and maintains the normal physiological status, in mammalian cells.DNA methylation is also involved in the regulation of imprinted gene expression and X-chromosome inactivation, and in the finetuning of tissue specific differentiation and development from stem cells.However, aberrant promoter hypermethylation of CpG islands leads to epigenetic silencing of multiple genes, including tumor suppressor genes, and has been recognized as an important mechanism involved in carcinogenesis.Furthermore, multiple genes have been shown to be methylated simultaneously (a condition termed the CpG island methylator phenotype: CIMP) in various types of human malignancies.This mechanism is a fundamental process involved in the development of many tumors.A comprehensive knowledge of the methylation profile of a given tumor may provide important information for risk assessment, diagnosis, monitoring, and treatments.Adult T cell leukemia/lymphoma (ATLL) is an aggressive malignant disease of CD4positive T lymphocytes caused by infection with human T-lymphotropic virus type I (HTLV-1).HTLV-1 causes ATLL in 3-5% of infected individuals after a long latent period of 40-60 years.Such a long latent period suggests that a multi-step leukemogenic/lymphomagenic mechanism is involved in the development of ATLL, although the critical event(s) involved in the progression have not been characterized in details.The pathogenesis of HTLV-1 has been investigated intensively in terms of the viral regulatory proteins HTLV-1 Tax and Rex, which are supposed to play key roles in the HTLV-1 leukemogenesis/lymphomagenesis, as well as the HTLV-1 basic leucine zipper factor (HBZ).The mechanism(s) underlying the progression of ATLL have been reported from various genetic aspects, including specific chromosome abnormalities and changes in the characteristic HTLV-1 Tax and Rex protein expression pattern, although the detailed mechanism(s) triggering the onset and progression of ATLL remains to be elucidated.In this chapter, the current state of knowledge about the epigenetic abnormalities that occur during the development and progression of T cell leukemia/lymphoma, especially during adult T-cell leukemia/lymphoma (ATLL), will be reviewed, as will the basic mechanism of epigenetic regulation of gene expression and various clinical aspects of T cell leukemia/lymphoma.In addition, the relevance of this knowledge to leukemia/lymphoma risk assessment, prevention and early detection will be discussed.

Epigenetic regulation on gene expression
The term "epigenetics" was coined by Conrad H. Waddinton in the 1940s, fusing the word "genetics" with "epigenesis".The classical definition proposed by Waddinton involves the heritability of a phenotype, passed on through either mitosis or meiosis.Recently, epigenetics has been proposed as "a stably heritable phenotype resulting from changes in a chromosome without alterations in the DNA sequence" (Berger et al., 2009).The pigenetic regulation of gene expression falls mainly into two categories, DNA methylation and histone modification (Figure 1).

Clinical characteristics of T-cell lymphoma
T-cell lymphoma is distinct clinicopathological entity classified by the WHO.T-cell lymphoma is a neoplasm with geographical variations in frequency, and the pathogenesis and clinical behavior, including the prognosis, are different from other lymphomas, such as B-cell lymphoma and Hodgkin's lymphoma.In this section, we mainly discuss the clinical features and management of T-cell lymphoma.

Clinical features of T-cell lymphoma 3.1.1 Epidemiology
The incidence of T-cell lymphoma demonstrates interesting geographical variations; in North America and Europe, about 5-10% of lymphomas are T-cell lymphomas (Anderson et al., 2002).However, in Asia, T-cell and natural killer (NK)-cell lymphomas account for 15-25% of all lymphomas (Au et al., 2005).The higher prevalence of T-cell lymphoma in Asia is reported to be influenced by endemic virus infections, such as human T-cell lymphotropic virus type-I (HTLV-1) and Epstein-Barr virus (EBV).The establishment of management recommendations by Asian oncologists in collaboration with international experts is urgently needed.

Clinical behavior of T-cell lymphoma
The WHO's classification includes 15 different T-cell lymphomas.Peripheral T-cell lymphoma not otherwise specified (PTCL-NOS), angioimmunoblastic T-cell lymphoma (AITL), and anaplastic large cell lymphoma (ALCL) account for 70-80% of T-cell lymphomas (Armitage et al., 1998).The other subtypes of T-cell lymphoma are rare entities.PTCL-NOS is a heterogeneous subtype that cannot be defined as another specific T-cell lymphoma.Both nodal and extranodal sites can be involved in this lymphoma.The nodal type can be well characterized histologically, but the extranodal type often does not show a www.intechopen.com

Accumulation of Specific Epigenetic
Abnormalities During Development and Progression of T Cell Leukemia/Lymphoma 137 definite histopathological pattern.In particular, cutaneous PTCL has specific histological features, and this lymphoma is defined as a distinct subtype; cutaneous T-cell lymphoma, in the WHO classification.Therefore, PTCL-NOS is often diagnosed by demonstration of a Tcell lineage.The relatively high proportion of patients with PTCL-NOS described in some series of T-cell lymphomas might thus reflect inadequate classification into other T-cell lymphoma subtypes.The clinical behavior of PTCL-NOS is not specific, but it generally has an aggressive clinical course similar to aggressive B-cell lymphoma, but the outcome of PTCL-NOS is poorer than that of aggressive B-cell lymphomas, such as diffuse large B-cell lymphoma (Tomita et al., 2007).The clinicopathological features of ALCL depend on the presence of anaplastic large cell lymphoma kinase (ALK).ALK-positive ALCL typicallys arise in 20-30-year-old patients, and mainly in males (Suzuki et al., 2000).The presentation can be both nodal and extranodal, involving the skin, bones, soft tissues, lungs, and liver.On the other hand, ALKnegative ALCL occurs primarily in elderly patients, and its presentation is usually nodal.The prognosis of ALCL is clearly divided into two groups by ALK expression, with the ALK-positive ALCL patients having a better prognosis than the ALK-negative patients (Suzuki et al., 2000).AITL occurs in elderly patients, who are often initially described as having an atypical reactive process with generalized lymphoadenopathy, skin rash, hepatosplenomegaly, fever and hypergammaglobulinemia.The prognosis of AITL is poor and comparable to that of PTCL-NOS, and many patients will die of infectious complications that may be the result of underlying immunodeficiency (Armitage et al., 1998).Other uncommon T-cell lymphomas include enteropathy-associated T-cell lymphoma (EATL), adult T-cell leukemia/lymphoma (ATLL), hepatosplenic T-cell lymphoma (10), and subcutaneous panniculitis-like T-cell lymphoma.EATL is associated with gluten-sensitive enteropathy and has a fatal clinical course.ATLL is caused by infection with HTLV-1, and this entity is also described in other sections in this issue.

Management of T-cell lymphomas 3.2.1 Initial assessment and staging of T-cell lymphomas
In the process of diagnosing T-cell lymphoma, the assessment of viral infection should be done as early as possible.The histological features and immunophenotype of ATLL are not specific among other T-cell lymphomas, and the detection of HTLV-1 is the only clue to the diagnosis of ATLL.The detection of EBV infection in the serum and lymphoma tissue is also important in T-cell lymphoma patients.In NK-cell lymphoma, the detection of EBV in tissues is an important diagnostic tool.When EBV is detectable in lymphoma or nonlymphoma cells, quantification of EBV DNA by quantitative PCR is a useful surrogate marker of the disease burden.Radiological procedures including CT and MRI are critical methods used in the staging of Tcell lymphomas.In addition, [18F]-fluorodeoxyglucose (FDG) has recently been reported to be avid in T-cell lymphoma patients, and PET/CT might be a useful procedure for the initial assessment of T-cell lymphoma patients (Kako et al., 2007).

Treatment 3.3.1 Initial chemotherapy
In the past several decades, conventional anthracycline-based chemotherapy has been the mainstay for the treatment of lymphoma, including T-cell lymphoma.The large international group trial established that cyclophosphamide, doxorubicin, vincristine, and predonisone (CHOP) was equally effective and less toxic than intensive second and third generation chemotherapy for aggressive lymphoma (Fisher et al., 1993).CHOP or CHOPtype chemotherapy is now considered to be the standard treatment for peripheral T-cell lymphomas, including PTCL-NOS, AITL and ALCL.However, the results of treatment with a CHOP-like regimen for T-cell lymphoma is poor, with 5-year overall survival (OS) of 10-45% (Armitage et al., 1998;López-Guillermo et al., 1998).Due to the low incidence of T-cell lymphoma, the optimum treatment regimen for T-cell lymphoma has not been studied prospectively in randomized controlled trials, and no effective regimen other than CHOP has been established.Although ALK-positive ALCL patients have a good prognosis even when treated using the CHOP regimen (Suzuki et al., 2000), other PTCL patients will need more efficacious regimens.Recently, modern dose-intense regimens have been investigated for aggressive lymphoma.A cyclophosphamide, doxorubicin, vincristine, dexamethasone (hyper CVAD) regimen was reported to be effective against Burkitt's lymphoma or mantle cell lymphoma, and a study of the hyper CVAD regimen for T-cell lymphoma patients showed a 3-year OS that was similar to that obtained using CHOP (49% and 43%) (Escalón et al., 2005).A French group showed that the cyclophosphamide, doxorubicin, vincristine, bleomycin, and prednisone (ACVBP) regimen was associated with a significant better 5-year OS than CHOP (46% vs 38%) in a randomized trial of patients with various types of aggressive lymphomas (Tilly et al., 2003).However, T-cell lymphoma patients accounted for only 15% of the cases evaluated in this study.Randomized trials will be necessary for more accurate assessment of the efficacy of this regimen for T-cell lymphoma.

Hematopoietic stem cell transplantation
Because of the generally poor outcome obtained with initial conventional chemotherapy, high-dose chemotherapy with autologous stem cell transplantation (ASCT) has been considered as a part of initial treatment for T-cell lymphoma.Numerous studies have shown favorable outcomes with low treatment-related mortality (TRM) (median OS was 50-70 months), particularly in advanced stage patients (Rodriguezet al., 2003(Rodriguezet al., & 2007;;Feyler et al., 2007).One study excluding ALK-positive ALCL patients, who are known to have a good prognosis with chemotherapy alone, showed that the median OS was 54 months, which was similar to the results of chemotherapy alone (Mounier et al., 2004).The trial conducted by the EBMT including 146 AILT patients reported that the median OS was 59 months, with low TRM (7%), indicating that ASCT should be considered as a useful treatment strategy for AITL patients (Kyriakou et al., 2008).Although most studies were retrospective and included ALK-positive ALCL patients, the favorable results and low toxicity indicated that ASCT is a promising strategy for PTCL patients.To clarify the patients who would benefit most from ASCT, further investigations in a prospective randomized setting are warranted.Allogeneic HSCT is considered as a salvage treatment for relapsed or refractory patients.Corradini et al conducted a Phase 2 study of 17 relapsed or refractory patients, and showed that there was a good outcome, with 64% and 80% 1-year disease-free survival (DFS) and OS respectively.Of interest, several patients responded to donor lymphocyte infusion, suggesting that there was a graft-versus lymphoma effect (Corradini et al., 2004).Another author reported their retrospective experience with seventy-seven PTCL patients who received an allogeneic HSCT.This study showed that the 5-year OS and event-free survival ATLL patients often present with opportunistic infections (Shimoyama et al., 1991).At present, the therapeutic outcomes of patients with acute or lymphoma type ATLL are still very poor.It is estimated that over one million peoples infected by HTLV-1 live in Japan (Yamaguchi et al., 2002) and that 15-20 million peoples are infected worldwide (Proietti et al., 2005).Only a small percentage of HTLV-1 carriers develop ATLL at a median age of 67 in Japan, whose median age is older than those in other countries.The cumulative risk of ATLL development in HTLV-1 carriers from 30 to 79 years of age was estimated to be 2.1% for females and 6.6% for males (Arisawa et al., 2000).Recently, the Joint Study on Predisposing Factors on ATLL Development (JSPFAD) Group performed a large scale cohort study between 2002 and 2008 for HTLV-1 carriers in order to clarify the risk factors for the development of ATLL.During this period, 14 cases out of 1,218 HTLV-1 carriers developed ATLL.This study revealed 4 major risk factors for the development of ATLL in HTLV-1 carriers using a multivariate analysis, i.e., high HTLV-1 proviral loads (in other words, an increase in HTLV-1 infected cells) in the PB, advanced age (over 40 years of age), the existence of a family history of ATLL, and detecting HTLV-1 antibody positivity during treatment for other diseases (Iwanaga et al., 2010).Familial ATLL cases were reported by several researchers (Miyamoto et al., 1985;Ratner et al., 1990;Wilks et al., 1993).Surprisingly, we experienced a family with accumulated familial ATLL, in which six of seven siblings (excluding one who died during World War II) developed acute type ATLL between 1978and 1989(Nomura et al., 2006).In HTLV-1 leukemogenesis, the HTLV-1 viral protein Tax activates nuclear factor-κB (NF-κB), represses p53, and is associated with various other protein-protein interactions (Yoshida, 2001).In particular, Tax plays an important role in the early phase of HTLV-1 leukemogenesis by immortalization of HTLV-1 infected T cells.On the other hand, cells expressing Tax are eradicated by the normal immune surveillance system by Tax-specific cytotoxic T lymphocytes (CTL).The accumulation of gene impairment finally results in leukemogenesis/lymphomagenesis of ATLL in HTLV-1 infected cells that escape from the CTL.However, ATLL cells frequently lack Tax expression or carry deletions in the Tax gene.Therefore, the Tax gene has been suggested to be non-essential for the proliferation of ATLL cells.On the other hand, HTLV-1 basic leucine zipper factor gene (HBZ) is expressed on the ATLL cells in all ATLL patients, and supports the proliferation of ATLL cells (Satou et al., 2006).HBZ is now considered to be vital for the leukemogenesis and progression of ATLL.Interestingly, there is a distinct mechanism of flower cell formation in ATLL cells which is a characteristic feature of the acute type ATLL demonstrated by Fukuda et al (2005).The multilobulated nuclear formation in ATLL cells is induced by overactivation of phosphatidylinositol 3-kinase signaling cascades resulting from disruption of phosphatidylinositol-3,4,5-triphosphate inositol phosphatases such as the phosphatase and tensin homolog deleted on chromosome 10 (PTEN) and Src homology 2 domain containing inositol polyphosphate phosphatase (SHIP).Moreover this aberrantly activated signaling pathway is suggested to have an essential role in the development of ATLL in patients.Recently, it has been reported that ATLL cells are derived from regulatory T (Treg) cells or helper T cell type 2 (Th2) cells both of which express CD4 and CD25 on their cell surface.Because ATLL cells express CC chemokine receptor 4 (CCR4) which is expressed on both Treg and Th2 cells, and forkhead/winged helix transcription factor (FoxP3) which is expressed on Treg cells in most ATLL patients, ATLL cells are now thought to be mainly of Treg cell origin (Karube et al., 2004).

Clinical features
The signs or symptoms frequently seen at the onset of ATLL include lymph node swelling, hepatosplenomegaly and skin lesions.ATLL patients also often suffer from abdominal symptoms such as abdominal pain or refractory diarrhea due to infiltration of ATLL cells into the gastrointestinal (GI) tract (Utsunomiya et al., 1988), and headache or disturbance of consciousness due to infiltration of ATLL cells into the central nervous systems (CNS).In addition, cough or dyspnea due to pleural effusion or lung infiltration of ATLL cells, abdominal distension due to lymph node swelling in the abdominal cavity, hepatosplenomegaly and/or ascites often distress ATLL patients.General fatigue, muscle weakness, constipation, and disturbance of consciousness are also seen, and are caused by the hypercalcemia associated with ATLL.Opportunistic infections are common in ATLL patients due to impairment of cellular immunity.In particular, fungal (cutaneous, pulmonary, oral, esophageal and meningeal) and protozoal (Pneumocystis carinii, Strongyloides stercoralis) infections are often seen at diagnosis, mainly in the acute or chronic, rather than the lymphoma type, of ATLL (Shimoyama et al., 1991).

Hematological and laboratory features
Leukocytes often increase from moderate to marked levels in leukemic type ATLL, while anemia and thrombocytopenia are rarely seen or mild, if they occur at all.Increases in the serum level of lactate dehydrogenase (LDH), serum calcium and soluble interleukin-2 receptor (sIL-2R) are frequently observed.Neutrophilia and/or eosinophilia are also observed due to the increased level of cytokines produced by the ATLL cells.Eosinophilia is a poor prognostic factor in ATLL patients (Utsunomiya et al., 2007).Hypercalcemia occurs more frequently in patients with aggressive ATLL, not only at the onset but also at relapse or upon transformation from an indolent to aggressive form.The mechanism underlying hypercalcemia is thought to be associated with the expression of parathyroid hormone-related peptides (PTHrP) (Watanabe et al., 1990) or tumor necrosis factor-β (TNF-β) (Ishibashi et al., 1991).In addition, over expression of receptor activator of nuclear factor-κB ligand (RANKL) on ATLL cells was found to correlate with hypercalcemia in ATLL patients (Nosaka et al., 2002).The tumor suppressor lung cancer 1 (TSLC1) gene was initially identified as a novel cell surface marker for ATLL.Afterward the expression of TSLC1 was found to be associated with tumor growth and organ infiltration of ATLL cells (Dewan et al., 2008).

Diagnosis and classification
ATLL is diagnosed as peripheral T-cell leukemia or lymphoma by cytology and the surface phenotype of tumor cells, and/or pathology combined with immunohistochemical findings.Positivity for anti-HTLV-1 antibodies in the sera is mandatory for a diagnosis of ATLL.Most ATLL cells have a CD4+CD8-surface phenotype, and other unusual phenotypes such as CD4+CD8+, CD4-CD8+, CD4-CD8-are seen in about 20% of ATLL patients.The patients with these unusual phenotypes have a poorer prognosis than the patients with the typical phenotype (Kamihira, et al., 1992).ATLL cells also express CD25, CCR4 and FoxP3.Histologically, the lymph nodes are occupied by diffuse proliferation of lymphoma cells with resultant destruction of the lymph node structure.Extranodal lesions such as those in the GI tract, skin or lungs should be diagnosed by histological examination.In addition to the presence of HTLV-1 antibodies in the sera, the detection of monoclonal integration of HTLV-1 proviral DNA in leukemia cells or tumor cells is necessary for a definite diagnosis of ATLL.
After the diagnosis of ATLL, subclassification of ATLL should be performed to determine the optimal therapeutic regimen.ATLL is divided into four clinical subtypes; the acute, lymphoma, chronic and smoldering types, according to the percentage of ATLL cells in the PB, the involvement of the CNS, bone, peritoneum, pleura and GI tract, and whether there are increases in the serum LDH and calcium (Table 1) (Shimoyama et al, 1991).An increase in the serum LDH and blood urea nitrogen, and a decrease in the serum albumin level are poor prognostic factors in patients with chronic type ATLL, so patients who have at least one of these poor prognostic factors have been considered to belong to the unfavorable subgroup (Shimoyama, 1994).The acute, lymphoma and chronic types with at least one of poor prognostic factors are considered to be aggressive ATLL, while chronic type, without any poor prognostic factors, and the smoldering types are called indolent ATLL.
Table 1.Diagnostic criteria for clinical subtype of ATLL A specific subtype of ATLL whose main lesions are limited to the skin, and does not have marked leukemic cells (<5%), a serum LDH level without exceeding 1.5-fold the normal upper limit, and a serum calcium level in the normal range was proposed as cutaneous type ATLL.The percentage of abnormal T-lymphocytes in the PB of such patients is less than 5% (Amano et al., 2008).

Progression/acute transformation
Indolent ATLL often progresses into acute type ATLL during the long period of the natural course of the disease.The rapid growth of lymph nodes, hepatosplenomegaly, and/or marked skin manifestations suddenly occur in previously indolent ATLL, often accompanied by marked leukocytosis, an increase in the serum LDH, sIL-2R and/or hypercalcemia.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.

Spontaneous regression
Few ATLL patients show spontaneous regression of tumors (Shimamoto et al., 1993).We experienced two chronic type ATLL patients, both of whom had a poor prognostic factor (increased serum LDH), who obtained a complete remission (CR) without any therapeutic intervention.In one patient, the systemic lymphadenopathy and ATLL cells in the PB disappeared, and the serum LDH level was normalized after surgical excision of an inguinal lymph node.However, he suffered from bone pain due to multiple bone lesions infiltrated by ATLL cells about 10 months after the CR.In another patient, the leukocytes and abnormal lymphocytes in the PB, and the serum LDH level gradually decreased to normal range.The ATLL cells in her PB had disappeared completely about 6 years after the diagnosis of ATLL without any therapy.She is now in an HTLV-1 carrier state, and has been free from ATLL for about 7 years after the complete disappearance of the ATLL cells in her PB.Although the mechanisms of spontaneous regression of ATLL have not been elucidated, it is suggested that the cytotoxic activity of peripheral mononuclear cells or the apoptosis of ATLL cells are associated with this phenomenon (Jinnohara et al., 1997;Matsushita et al., 1999).Clarification of this interesting phenomenon might be useful for the development of new immunological therapy for ATLL patients.

Therapy
Treatment for patients with ATLL differs according to the clinical subtypes.It therefore is very important to make an accurate diagnosis of the clinical subtype of ATLL in order to ensure that the appropriate therapy is selected.In patients with indolent ATLL including those with the smoldering type or the chronic type without any unfavorable prognostic factors, watchful waiting is the standard of care in Japan except when the patients are suffering from symptomatic skin lesions.Generally, intensive combination chemotherapy for aggressive ATLL has been performed immediately after the diagnosis because the prognoses of aggressive ATLL are poorer than those of other non-Hodgkin's lymphomas (NHL) free from HTLV-1 infection (Shimoyama et al., 1988).The results of chemotherapy in studies performed by the Japan Clinical Oncology Group-Lymphoma Study Group (JCOG-LSG) from the 1980's to early 1990's were unsatisfactory for ATLL.The CR rate was 17-42%, and the median OS time was 5-13 months, and the OS rate at 3 years was only 13-24% (Uozumi, 2010).Recently, Tsukasaki et al (2007) reported the results of a randomized phase III trial for aggressive ATLL.They revealed that the CR rate was higher in the patients treated with sequential combination chemotherapy consisting of VCAP (vincristine, cyclophosphamide, doxorubicin, and prednisone), AMP (doxorubicin, ranimustine, and prednisone), and VECP (vindesine, etpoposide, carboplatin, and prednisone) (mLSG15) than in those treated with biweekly CHOP (vincristine, cyclophosphamide, doxorubicin, and prednisone: bi-CHOP) (40% vs 25%, respectively).Furthermore, the OS rate at 3 years was higher in the mLSG15 arm than in the bi-CHOP arm (24% vs 13%, respectively) (Tsukasaki et al., 2007).On the other hand, Bazarbachi et al (2010) reported that excellent results were obtained using combination therapy with zidovudine (AZT) and interferon-α (IFN) for ATLL patients.The OS rate at 5 years was 46% for their 75 patients who received first-line antiviral therapy.In particular, the OS rate at 5 years for patients with the chronic and smoldering types of ATLL was 100%.However, the results for aggressive type ATLL obtained using AZT/IFN therapy were inferior to those obtained during the JCOG-LSG study (JCOG9303, JCOG9801) (Yamada et al., 2001;Tsukasaki et al., 2007).Nevertheless, as the results of chemotherapy for aggressive ATLL are unsatisfactory, new strategies using approaches other than conventional chemotherapy are needed for ATLL to improve the survival of the patients.We previously reported that allogeneic hematopoietic stem cell transplantation (allo-HSCT) was useful for aggressive ATLL (Utsunomiya et al., 2001).Following our report, many other researchers reported the possibility of long-term survival in ATLL patients who received allo-HSCT using conventional or reduced intensity conditioning (Fukushima et al., 2005;Okamura et al., 2005;Shiratori et al., 2008;Hishizawa et al., 2010).A graft-versus-Tax (Gv-Tax) response in ATLL patients after allo-HSCT was demonstrated by Harashima et al (2004).The Gv-Tax response, which has been suggested to induce a graft versus-ATLL (Gv-ATLL) effect may bring about the eradication of not only ATLL cells but also of HTLV-1 infected cells in general (Okamura et al., 2005;Yonekura et al., 2008).New agents, especially an anti-CCR4 antibody (KW-0761) are promising for ATLL therapy.Recently, promising results for relapsed ATLL patients who had been treated by intravenous administration of KW-0761 indicated that the overall response rate was 31% in a phase I study (Yamamoto et al., 2010) and 50% in a phase II study (Ishida et al., 2010).Other novel agents, such as lenalidomide (a thalidomide analogue) and bortezomib, which inhibits proteasome and thereby inhibits activation of NF-κB, are now being evaluated in clinical trials for relapsed ATLL in Japan.In addition, immunotherapy using dendric cells stimulated by Tax peptides is now being prepared for ATLL patients who had previously obtained remission by chemotherapy.In conclusion, ATLL presents diverse features, and the mechanisms of leukemogenesis induced by HTLV-1 development and the progression of ATLL have not been well elucidated.Clarification of these mechanisms will therefore give ATLL patients a chance to obtain a cure.Furthermore, our final goals are not only to cure ATLL patients, but also to completely eradicate HTLV-1 by preventing HTLV-1 infection or by eradicating infections once they are established.

Modulation of the expression profile in the immune system through epigenetic mechanism
Epigenetic mechanisms control the development and differentiation, and maintain the normal physiological status in mammalian cells, and epigenetic events link a subjects' genotype to their phenotype.Epigenetic regulatory mechanisms are a central system to control the differentiation and function of the immune system and to ensure an appropriate gene expression profile in immune cells (Natoli G, 2010).This mechanism changes the gene expression profile, permitting cells to adapt to multiple environmental www.intechopen.comAccumulation of Specific Epigenetic Abnormalities During Development and Progression of T Cell Leukemia/Lymphoma 145 pressures.Pathogenic factors may be considered such an environmental pressure (Arens & Schoenberger;2010).Consequently, cellular differentiation and adaptation might be considered as an epigenetic phenomenon.Many of the recent epigenetic investigations have focused on DNA methylation, histone modifications and chromatin remodeling.Non-coding RNAs, such miRNAs, also play important roles in epigenetic pathways (Thai et al. 2010).

Epigenetic abnormalities in leukemia and lymphoma
Lymphoma and leukemia, as well as other cancers, have been thought to be predominantly induced by acquired genetic changes such as mutations, deletions, and amplifications of genes and chromosome translocations.However, it is now becoming clear that microenvironment-mediated epigenetic alterations also play important roles.Although many genetic changes have been reported, it is difficult to discriminate cause from consequence.It is also unclear whether genetic or epigenetic changes occur first.Recent data suggest that cancer has a fundamentally common basis that is grounded in a polyclonal epigenetic disruption of stem/progenitor cells, mediated by 'tumor-progenitor genes'.Furthermore, tumor cell heterogeneity is due, in part, to epigenetic variation in progenitor cells, and epigenetic plasticity, together with genetic lesions, drives tumor progression (Feinburg et al, 2006).The epigenetic disruption of key genes is supposed to occur at the earliest stage of cancer development.Some of the most convincing evidence for epigenetic disruption of progenitor cells derives from the ubiquitous nature of genome-wide hypomethylation, which is present in almost of all malignant tumors.In addition, genesilencing induced by hypermethylation of genes involved in DNA repair (MGMT, hMLH1), cell cycle progression (p16INK4a, p15INK4b, p14ARF), signal transducing molecules (SHP1), apoptosis (DAPK) and cell adhesion (CHD1, HCAD) (Flanagan, 2007) is also common.Therefore, non-neoplastic, but epigenetically disrupted, stem/progenitor cells might be a crucial target for cancer risk assessment and chemoprevention.

Frequent gene silencing of hematopoietic cell-specific protein tyrosine phosphatase (SHP1) in hemetopoietic cell malignancies
Genome-wide studies of gene expression on a genomic scale using cDNA microarrays make it easy to measure the transcription levels of almost every gene at once.Various types of leukemia/lymphoma have been analyzed using cDNA microarrays to investigate the molecular basis of leukemogenesis/ lymphomagenesis.From the cDNA microarray analyses of gene expression pattern of the human NK/T cell line (NK-YS), followed by comprehensive and systematic tissue microarrays, RT-PCR and Western blotting analysis, it has been demonstrated that strongly decreased expression of hematopoietic cell specific protein-tyrosine-phosphatase SHP1 mRNA was present in malignant cells (Oka et al., 2001).A further analysis using standard immunohistochemistry and tissue microarrays, which utilized 207 paraffin-embedded specimens of various kinds of malignant lymphomas, showed that 100% of NK/T lymphomas and more than 95% of malignant leukemia/lymphoma patient specimens of DLBCL, follicular lymphoma (FL), Hodgkin's lymphoma (HL) (Hodgkin's disease (HD)), mantle cell lymphoma (MCL), peripheral T-cell lymphoma (PTCL), ATLL and plasmacytoma were negative for SHP1 protein expression.The promoter region of the SHP1 gene has been revealed to be highly methylated in patient samples of adult T cell leukemia (methylation frequency: 90%), natural killer (NK)/T cell lymphoma (91%), diffuse large B-cell lymphoma (93%), MALT lymphoma (82%), mantle cell lymphoma (75%), plasmacytoma (100%) and follicular lymphoma (96%).The methylation frequency was significantly higher in high grade-MALT lymphoma cases (100%) than in low grade-MALT lymphoma cases (70%), correlating well with the frequency of the lack of SHP1 protein in high grade-(80%) and low grade-MALT lymphoma (54%) (Oka et al., 2002;Koyama et al., 2003).This suggests that the SHP1 gene silencing with aberrant CpG methylation is related to the progression of lymphoma, in addition to the malignant transformation.Furthermore, the promoter methylation of the SHP1 gene was clearly correlated with the clinical stage, such as complete remission or relapse.Loss of heterozygosity with microsatellite markers near the SHP1 gene was shown in 79% of informative ALL cases.These findings indicate that the SHP1 gene is a relevant novel biomarker of a wide range of hematopoietic malignancies.Additionally, these results suggest that loss of SHP1 gene expression plays an important role in multistep lymphomagenesis/leukemogenesis.SHP1 negatively regulates the Janus kinase/signal transducer and activator of transcription (Jak/STAT) signaling pathway (Chim et al., 2004a;Chim et al., 2004b).SHP1 in myeloma showed hypermethylation, with constitutive STAT3 phosphorylation.Demethylating reagent-treated myeloma samples showed restored SHP1 expression in accordance with down-regulation of phosphorylated STAT3 (Chim et al., 2004a).SHP1 methylation thus leading to the induction of epigenetic activation of the Jak/STAT pathway might play a key role in the pathogenesis of myeloma.Similarly, frequent methylation of SHP1 was observed in mantle cell and follicular lymphomas (Oka et al., 2001(Oka et al., & 2002;;Chim et al., 2004c) and also in acute myeloid leukemia (Oka et al., 2001;Chim et al., 2004b).The hypermethylation of SHP1 led to the activation of the Jak/STAT signaling pathway, along with the upregulation of cyclin D1 and BCL2, and could be the basis for the lymomagenesis of follicular lymphoma (Koyama et al., 2003;Chim et al., 2004c).

Epigenetic changes induced by virus infection
More than 20% of cancers have been causally linked to human pathogens (Zur Hausen, 2009).Why virus infection is sometimes controlled, and on the other occasions leads to the progression to malignant tumors is still mystery.However, recent evidence suggests that epigenetic changes induced by infection play a causative role.Oncogenic viruses have been revealed to increase DNA methylation activity and decrease histone acetylation activity (Flanagan, 2007).The latent membrane protein 1 (LMP-1), one of the virus proteins of EBV, has been shown to be an oncoprotein with transforming activity.LMP-1 activates DNMT1, DNMT3a and DNMT3b to initiate epigenetic alterations, followed by hypermethylation and gene silencing of the E-cadherin gene (Tsai et al., 2002).Human epithelial cells expressing LMP-1 have been shown to have higher invasive activity, in accordance with reduced expression of the E-cadherin gene (Kim et al., 2000).Integration-defective HIV-I was shown to increase DNMT1 expression, followed by increased methylation of CpG islands in the promoter region of the p16 INK4A and IFN-gamma genes to induce gene silencing (Fang et al., 2001;Mikovits et al., 1998).Overall increases in DNA methyltransferase activity in malignant cells compared with normal tissues is also common in non-virus-related cancers (Esteller, 2006) The ability to alter histone modifications and chromatin structure is also common to many oncogenic viruses, including EBV, HPV, adenoviruses and HTLV-1.EBV nuclear antigens EBNA2 and EBNA 3c alter histone acetylation by interacting with p300/CBP, PCAF histone acetyltransferase (HAT) complexes or with histone deacetylase (HDAC), respectively (Wang et al., 2000;Knight et al., 2003).The HPV E6 oncoprotein binds and inhibits the histone acetyltransferase activity of the p300/CBP complex (Patel et al., 1999).The HTLV-1 Tax protein also interacts with the p300/CBP complex to mediate transcriptional repression (Kwok et al., 1996).Disruption or alteration of p300/CBP histone acetyltransferase activity is common to many oncogenic viruses, suggesting that it may be one of the critical early events in virus-induced tumorigenesis.Further evidence of the early involvement of p300/CBP in various non-viral cancers has also been observed, suggesting that abrogation or perturbation of the histone acetyltransferase activity of p300/CBP may be one of the critical early events in all malignant tumors (Flanagan, 2007).

Accumulation of epigenetic abnormalities during the development and progression of ATLL
ATLL is an aggressive malignant disease of CD4-positive T lymphocytes caused by infection with HTLV-1 (Poiesz et al., 1980;Hinuma et al., 1981).HTLV-1 causes ATLL in 3-5% of infected individuals after a long latent period of 40-60 years (Tajima et al., 1990).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 its progression have not been well characterized.The pathogenesis of HTLV-1 has been intensively investigated in terms of the viral regulatory proteins HTLV-1 Tax and Rex, which are supposed to play key roles in the HTLV-1 leukemogenesis/lymphomagenesis, as well as the HTLV-1 basic leucine zipper factor www.intechopen.comT-Cell Leukemia 148 (HBZ) (Matsuoka et al., 2003(Matsuoka et al., , 2007;;Gaudray et al.2002).The mechanism responsible for the progression of ATLL have been investigated from various genetic aspects, including specific chromosome abnormalities (Okamoto et al., 1989;Oka et al.1992Oka et al. , 2006;;Ariyama et al.1999;Fujimoto et al., 1999), changes in the characteristic HTLV-1 Tax, Rex and HBZ protein expression patterns (Oka et al., 1992;Selgrad et al., 2009) and aberrant expression of the SHP1 (Oka et al., 2002(Oka et al., , 2006)), P53 (Yamato et al., 1993;Tawara et al., 2006), DRS (Shimakage et al. 2007), and ASY/Nogo (Shimakage et al. 2006) genes, although the detailed mechanisms triggering the onset and progression of ATLL remains to be elucidated.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., , 2002;;Koyama 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.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).It will be of interest to determine whether there is a direct link between HTLV-1 induction of DNMTs causing CIMP and hypermethylation of specific target genes, and how or what kind of viruses induce deregulation of the epigenetic machinery.Such discoveries may provide new insights into the understanding of the molecular mechanisms responsible for virusinduced lymphomagenesis and leukemogenesis.The HTLV-1 Tax protein has been demonstrated to activate the nuclear factor-κB (NF-κB) and Akt pathways as major cellular pro-survival pathways (Yoshida, 2001).However, Tax transcripts are detected in only about 40% of transformed ATLL cells and are sometimes mutated.On the other hand, it has been demonstrated that the Hbz transcript is ubiquitously expressed in all ATLL cells, and possesses a pro-proliferative function in cells (Satou et al., 2006).It has therefore been proposed that Tax initiates transformation, while HBZ is required to maintain the transformed phenotype late in ATLL when Tax expression is extinguished (Matsuoka & Jeang, 2011).During malignant progression, tumor cells need to acquire novel characteristics that lead to uncontrolled growth and reduced immunogenicity.The loss of Tax expression in vivo could facilitate the escape of HTLV-1 infected cells from CTL-surveillance to induce disease progression.In the Bovine Leukemia Virus (BLV)-induced ovine (sheep) leukemia model, silencing of viral gene expression has been proposed as a mechanism leading to immune evasion (Merimi et at., 2007).They showed that there was a correlation between the complete suppression of provirus expression and tumor onset, providing experimental evidence that virus and Tax silencing are critical, if not mandatory, for the progression to overt malignancy.This suggests that epigenetic and/or genetic changes in the host genome induced by HTLV-1 infection are crucial for the onset and progression, independent of virus genome expression.This raises questions about whether it might be possible to maintain the leukemic phenotype, on for cells to progress to ATLL without Tax expression.One possibility is that the genetic changes are associated with multipolar mitosis and aneuploidy.Aberrant centrosome replication is linked to oncogenesis, disregulating the intact spindle assembly checkpoint, accurate centrosome cycle and proper cytokinesis (Chi & Jeang, 2007).A second possibility is that there is aberrant expression of miRNAs (microRNAs) in ATLL leukemic cells, which occur independent of Tax expression.Yeung et al. reported that the tumor suppressor protein, TP53INP1, in HTLV-1 infected/transformed cells was targeted for repression by upregulated expression of miR-93 and miR-130b (Yeung et al., 2008).Pichler et al also reported that TP53INP1 was targeted in HTLV-1 infected/transformed cells by miR-21, -24, 146a and -155 (Pichler et al., 2008).Bellon et al described that ATLL cells show increased expression of miR155 (Bellon et al., 2009).These aberrant expression levels of onco-miR may disregulate downstream gene expression.A third possibility is that aberrant gene expression induced by epigenetic abnormalities, including aberrant DNA methylation, abnormal changes in histone modifications and dysregulation of chromatin remodeling, are maintained by daughter cells though epigenetic machinery.

Possible link to host-pathogen interaction
Experimental interspecies-transmission of BLV to sheep shows the shorter latency period preceding disease onset: leukemia occurs usually 1-4 years after infection in contrast to 4-10 years in cows.In addition, the incidence of virus-induced leukemia is much higher: almost all infected sheep will succumb within normal life time compared to only about 5% in cattle, suggesting that it is related to the lack of natural transmission of BLV to sheep (Florins et al., www.intechopen.comT-Cell Leukemia 150 2008).In nature it is often observed that interspecies transmission of viruses results in a high incidence of disease in the new host.Genetic analyses of several human and simian T-cell leukemia virus type-I (HTLV-1/STLV-1) strains of African and Asian origin suggest recent interspecies transfer between species within primate genera, including humans.The phylogenetic analyses suggest that at least three independent human-simian exchanges have occurred during the evolution of these retroviruses (Dekaban et al., 1996).The incidence of ATLL within normal lifetime is about 5%, suggesting that HTLV-1 is in the process to establish a new relationship to human as a natural host.Elucidation of symbiotic evolution mechanisms may provides new insights to find out the strategy to reduce the virulence of HTLV-1 and suppress the onset of diseases.

Epigenetic therapy for leukemia/ lymphoma
Abnormalities of the epigenetic machinery have been associated with a broad range of diseases, including hematologic disorders and malignant leukemia/lymphoma.The malignancies have specific epigenetic profiles related to their histological type, and show many common phenotypes such as self-sufficiency of growth signals, resistance to antiproliferative or pro-apoptotic signals, and so on.As previously reported, epigenetic markers can be used for various clinical applications, including for determing the risk of the onset and progression, for early detection, prediction of prognosis, and for predicting treatment outcomes and evaluating the response to treatment.Moreover, there are already several systems with high sensitivity for detecting epigenetic profiles, such as the methylation-specific polymerase chain reaction (MSP) assay, which have been developed using leukemia/lymphoma samples (Oka et al., 2002;Sato et al., 2010).The epigenetic modifications are characterized by reversible reactions.On the basis of this point, inhibitors to reverse these modifications as therapeutic interventions have been developed and exploited, and good results have been reported for various malignant leukemias/lymphomas.It is important to determine why T cell leukemia/lymphoma shows a worse prognosis than other disease, and to use this information to design a effective treatment.It is noteworthy that epigenetic therapy is now regarded as an innovative approach to the treatment of T cell leukemia/lymphoma (Piekarz et al., 2009a).In fact, treatment of tumor cells with epigenetic drugs can induce a range of antitumor effects, including apoptosis, cell cycle arrest, differentiation and senescence, modulation of immune responses, and angiogenesis (Bolden et al., 2006).The current drugs targeted for epigenetic mechanisms are categorized as either histone deacetylase (HDAC) inhibitors (HDACi) such as vorinostat, romidepsin and DNA methyltransferase (DNMT) inhibitors, such as 5-aza-2'-deoxycytidine (DAC) or 5azacytidine (5-AC).HDACi have diverse structures, and include sodium butyrate, vorinostat, MS-275, TSA, and FK228 (Prince et al., 2009).However, regardless of their structures, similarities have been observed with regard to their efficacy, and their timing-and dose-dependence, although some profiles on gene expression induced by HDACi seem to be agent-specific (Gray et al., 2004;Peart et al., 2005).Several HDACi have also been reported to predominantly improve the patient prognosis (Prince et al., 2009).However, the mechanism responsible for the marked efficacy of HDACi in T cell lymphoma is not yet understood, nor is there an understanding of the differences among the various HDACi.Piekarz et al. speculated that the responsive subset of T cell lymphomas has its origin in an as-yet unknown chromosomal rearrangement that recruits the class I HDACs to the promoter of a gene, and T cell lymphoma is therefore distinctly susceptible to different therapeutic interventions that affect HDACs (Piekarz et al., 2009b).In particular, Vorinostat (suberoylanilide hydroxamic acid, SAHA), which is a hydroxamic acid derivative that inhibits both class I and II HDACs, showed a good response for the treatment of relapsed and refractory cutaneous T-cell lymphoma (CTCL) (O'Connor et al., 2006;Mann et al., 2007;Duvic et al., 2007;Olsen et al., 2007;Garcia-Manero et al., 2008).Romidepsin (depsipeptide, FR901228, FK228, NSC 630176) is generally classified as a broad-spectrum inhibitor, as it inhibits class II enzymes.Romidepin was the first HDACi reported to show efficacy as monotherapy (complete or partial response) in patients with PTCL and CTCL (Piekarz et al., 2001).Favorable responses have been confirmed in CLL (Byrd et al., 2005;Dai et al., 2008;Inoue et al., 2009), CTCL (Piekarz et al., 2009b;Bates et al., 2010;Whittaker et al., 2010), and in additional PTCL patients (Bates et al., 2010;Piekarz et al., 2011).Panobinostat (LBH589) induces clinical responses in patients with refractory CTCL (Ellis et al., 2008).Peart et al. described that the specific attributes of each individual HDACi could be clarified, and that "matching" an individual HDACi to particular tumors or genetic profiles might help improve the clinical responses (Peart et al., 2003).The two main analogs of DNMT inhibitors, such as DAC and 5-AC, are incorporated into DNA to trap and target DNMTs for degradation.The subsequent absence of these enzymes during DNA synthesis causes hypomethylation, and finally, reactivation of silenced gene expression in the daughter cells.The activated gene expression has effects on multiple pathways, contributing to a clinical response (Yoo et al., 2006).However, caution should be exercised, because the hypomethylation resulting from treatment these drugs can also likely activate oncogenes that are generally known to be silenced (e.g., COX2, EGFR, etc) (Toyota et al., 2005).Recent data show that hypomethylation by treatment with a single DAC is insufficient for the induction of gene expression (Si et al., 2010).Therefore, combination therapies using DNA demethylating agents with HDACi are well established.Indeed, HDACi enhance the activation of aberrantly methylated tumor suppressor gene promoters in tumor cells by DNA demethylating agents (Cameron et al., 1999;Steiner et al., 2005).These results suggest that potentiation of DAC-mediated gene induction by HDACi may be more complex than mere additive activities.However, the previous trials have mostly involved patients with AML and MDS (Silverman et al., 2009), not including those with T cell leukemia/lymphoma.Approximately 30-40% cases of PTCL-NOS express CCR4+, and CCR4 expression is an unfavorable prognostic factor (Ohshima et al., 2004;Ishida et al., 2004).Additionally, PTCL originating from a CCR4+ Treg cell often shows a tendency to be ''PTCL-NOS with genomic alterations'' (Ishida et al., 2011).Tumor cells from most ATLL patients are characterized by the Treg phenotype膅CD4+CD25+CCR4+FOXP3+䐢 (Yoshie et al., 2002;Karube et al., 2008).Consequently, anti-CCR4 mAbs (KW-0761) have been developed, and have shown notable anti-tumor effects (Yamamoto et al., 2010;Ishii et al., 2010).Interestingly, a recent investigation showed that the CCR4 expression on human CD4 + T cells is regulated by histone H3 acetylation and methylation (Singh et al., 2010).In ATLL, it was noted that the indolent type is associated with a worse survival (mean survival time: 4.1 years) (Takasaki et al., 2010), and the proliferation of HTLV-1 infected cells seems to determine the viral burden during the carrier state (Matsuoka et al., 2011).These reports suggest that early detection and treatment are essential for preventing transformation, or for decreasing the tumor burden in patients with the disease.Tax expression is regulated by the SUV39H1 histone methyltransferase (Kamoi et al., 2006) and HDAC1 (Ego et al., 2002), which negatively regulate the viral gene expression.These findings indicate that the presence of epigenetic abnormalities, including those that occur as a result of Tax regulation, play crucial roles in the pathogenesis of ATLL.A previous report showed that a histone deacetylase inhibitor, valproate, reduced the HTLV-1 proviral load in HAM/TSP through induction of tax gene expression and subsequent activation of CTLs (Lezin et al., 2007).However, it is important to note that the downstream effectors affected by these epigenetic agents have not been elucidated, although their primary enzymatic targets are known.In addition, it is necessary to confirm the optimal dosing schedule, potency, pharmacology, and longterm toxicity for each cell type.Recent reports have evaluated additional combinations of HDACi with other agents, such as anthracyclines, in patients with AML and MDS (Zxu et al., 2010) and AMG 655 (anti-TRAIL receptor 2 antibody) in patients with various B cell lymphomas (National Cancer Institute (NCI), USA; http://www.cancer.gov).It appears that combination therapy using epigenetic agents with another therapy, such as immunotherapy, will make it possible to create an effective treatment strategy for intractable T cell leukemia/lymphoma.Additional larger studies of epigenetic therapy in subjects with intractable T cell leukemia/lymphoma are warranted.

Conclusions and perspective
Increased activity of DNA methyltransferases and decreases in p300/CBP-mediated histone acetylation are common in both virus-induced and non-viral malignancies, which suggests that epigenetic therapy would be effective for a wide range of malignancies.Aberrant DNA methylation has been shown to be the most consistent molecular changes present in many neoplasms.Hypermethylation of specific target genes, which can be detected at various stages and in different types of lymphomas and leukemias, can be detected with high sensitivity and accuracy.In the near future, we hope to be able to identify the specific signature of the methylation profile and biomarkers of hypermethylated genes for each specific type and stage of malignancy.Moreover, some epigenetic markers might be present prior to the development of lymphoma and leukemia.Thus, epigenetic markers may crucial for identifying the risk of leukemia/lymphoma development and also indicate the possibility of cancer prevention for such high-risk patients.Epigenetic changes, in contrast to genetic changes, can be easily reversed by the use of therapeutic interventions at various stages.The hypermethylated genes found in various cancers, in addition to leukemia/lymphoma, seem to be particularly sensitive to reactivation by demethylating reagents and HDACi.Therefore, restoration of multiple gene functions at the same time may be possible by therapeutic targeting of DNA methylation and histone acetylation.This could have profound implications for the diagnosis and treatment of malignancies.The newer technologies that enable the global analyses of the epigenome are developing with remarkable speed, and include methods such as ChIP-on-chip (Chromatin ImmunoPrecipitation with microarray) and ChIP-sequencing, with deep sequencing by next generation sequencers for mapping global methylation and chromatin modifications, which will provide information about the landscape of infection-induced alterations, and about the www.intechopen.comAccumulation of Specific Epigenetic Abnormalities During Development and Progression of T Cell Leukemia/Lymphoma 153 dynamic nature of microbe-host interactions and the human epigenome itself with regard to the various diseases.Such findings will greatly assist in improving human health.
N: normal upper limit, CNS: central nervous system, GI tract: gastrointestinal tract.* : No essential qualification except terms required for other subtype(s).*2: No essential qualification if other terms are fulfilled, but histology-proven malignant lesion(s) is required in case abnormal T-lymphocytes are less than 5% in peripheral blood.*3: Accompanied by T-lymphocytosis (3.5×10 9 /l or more).*4: In case abnormal T-lymphocytes are less than 5% in peripheral blood, histology-proven tumor lesion is required.

Fig. 2 .
Fig. 2. Natural course from infection of human T lymphotropic virus type-I (HTLV-1) 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.