•The combination of DNA demethylating agents and EZH inhibitors synergistically suppressed tumor cell growth in ATL.•DUSP5 is silenced in HTLV-1–infected cells via DNA and H3K27 methylation and the ...reactivation dephosphorylates ERK and inhibits cell growth.
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Adult T-cell leukemia/lymphoma (ATL) is a malignancy of mature CD4+ T cells caused by human T-cell lymphotropic virus type 1 (HTLV-1)–induced T-cell transformation. After infection with HTLV-1, it takes several decades for HTLV-1 carriers to develop ATL. The prognosis of ATL remains poor despite several new agents being approved in the last few years. Recently, it has been noted that epigenetic abnormalities, both DNA methylation and trimethylation at histone H3Lys27 (H3K27me3), contribute to ATL leukemogenesis. Here, we investigated the effect of combination treatment with DNA demethylating agents (azacitidine AZA, decitabine (DAC), and OR-2100 (OR21), which is a silylated derivative of DAC) and inhibitors of enhancer of zeste homolog 2 (EZH2) (EPZ-6438 and DS-3201b), which catalyze trimethylation of H3K27, in ATL. The combination of DAC and OR21 but not AZA with EZH inhibitors exhibited synergistic anti-ATL effects in vitro and in vivo, concomitant with DNA demethylation and reduction of H3K27me3. The combination induced gene expression reprogramming. Dual-specificity phosphatase 5 (DUSP5), an extracellular signal-regulated kinase (ERK)–specific phosphatase, was identified as a key molecule that mediated the inhibitory effect of combination treatment by inactivating the ERK signaling pathway. DUSP5 was downregulated by DNA methylation and H3K27me3 accumulation in the promoter region in HTLV-1–infected cells from patients with ATL during ATL leukemogenesis. The present results demonstrate that dual targeting of aberrant DNA and histone methylation synergistically suppresses tumor cell growth by restoring DUSP5, and that dual targeting of aberrant DNA and histone methylation is a feasible therapeutic approach for ATL.
Hairy cell leukemia (HCL) is a rare B-cell lymphoid malignancy that is difficult to distinguish from other morphological variants. The frequency of HCL has not been determined accurately in Japan. ...Recent studies revealed that the BRAF V600E mutation is the causal genetic event in HCL. We assessed the BRAF mutation in Japanese patients with HCL and related diseases using the quenching probe (QP) method, a single-nucleotide polymorphism detection system, and evaluated the incidence rate of HCL among Japanese patients with chronic lymphocytic leukemia, and related diseases. We identified 18 cases (33.3%) harboring the BRAF mutation among 54 patients diagnosed with, or suspected of having HCL. Of BRAF V600E-positive patients, 7 were only detected using the QP method, not by direct sequencing, whereas 11 were positive using both tests. In a larger cohort of Japanese patients diagnosed with chronic lymphoid leukemia or related diseases, the frequency of HCL was 4%. Patients with the BRAF V600E mutation had a significantly higher frequency of neutropenia, thrombocytopenia, and elevated soluble interleukin-2 receptor and common B-cell surface markers than patients without the mutation. Our results confirm that BRAF V600E-positive HCL is a relatively rare disorder in the Japanese leukemia patient population.
Pulmonary alveolar proteinosis (PAP) is a rare disease characterized by the accumulation of eosinophilic periodic acid Schiff-positive material in the intra-alveolar and bronchiolar spaces. Tyrosine ...kinase inhibitors, including imatinib, nilotinib, and dasatinib, have shown excellent efficacy in the treatment of chronic myeloid leukemia (CML). We report a case of acquired PAP in a patient with CML receiving tyrosine kinase inhibitors. A 67-year-old man with CML presented with progressive back pain 5 months after starting imatinib treatment. Acquired PAP was diagnosed based on physical, radiographic, and histopathological findings. The presence of granulocyte-macrophage colony-stimulating autoantibodies suggested that autoimmune mechanisms were involved in the pathogenesis. Interestingly, PAP developed in association with imatinib and dasatinib administration, but not with nilotinib treatment. The patient died of refractory leukemia in lymphoid blast crisis with a newly emerged T315I mutation. Although the incidence is very rare, imatinib and dasatinib associated with PAP development has been reported. Meanwhile, PAP in nilotinib-treated patients has not been reported. Our observation in one patient receiving multiple TKIs suggests that nilotinib may be safer than imatinib or dasatinib in avoiding the development or exacerbation of PAP.
Purpose
The 14th Japan–Korea joint symposium on cancer and aging research was held at an auditorium of Saga University, Japan, May 31–Jun 2, 2018. Participants presented 31 oral and 21 poster ...presentations, two lectures at a luncheon seminar, plus special lectures from two Korean Emeritus Professors and founders of our joint symposia. The essential parts of the lectures are reviewed here.
Results
This Symposium was called Japan–Korea, because the host country comes first. Our symposia are organized every 18 months and the program includes keynote and plenary lectures, and oral and poster presentations. (1) Subjects related to cancer development at this symposium were: prostate cancer progression, molecules activating GSK3β, suppressing the activation of cancer stem cells, profiling human B cell receptor repertoires, and hereditary gastrointestinal cancer syndrome. (2) Subjects related to treatment were: G-quadruplex ligands for glioma stem cells, tankyrase inhibitor for colorectal cancer, and eradication of ATL. (3) Cancer prevention subjects were: physical adsorption of EGCG to cell membrane, inhibition of immune evasion of cancer cells with EGCG, and prevention with antidiabetic agents. (4) Aging subjects were life span extension with Toll-like receptor 5 vaccine and reversal of senescence with inhibitors of ATM and ROCK. (5) The results of epidemiology focused on aldehyde dehyrogenase-2 and alcohol consumption.
Conclusion
The 14th symposium demonstrated the cutting-edge of presentations with discussion of numerous ideas by the participants.
: In the normal human life span, there occur lifestyle‐related diseases that may be preventable with nontoxic agents. This paper deals with the preventive activity of green tea in some ...lifestyle‐related diseases. Green tea is one of the most practical cancer preventives, as we have shown in various in vitro and in vivo experiments, along with epidemiological studies. Among various biological effects of green tea, we have focused on its inhibitory effect on TNF‐α gene expression mediated through inhibition of NF‐κB and AP‐1 activation. Based on our recent results with TNF‐α‐deficient mice, TNF‐α is an endogenous tumor promoter. TNF‐α is also known to be a central mediator in chronic inflammatory diseases such as rheumatoid arthritis and multiple sclerosis. We therefore hypothesized that green tea might be a preventive agent for chronic inflammatory diseases. To test this hypothesis, TNF‐α transgenic mice, which overexpress TNF‐α only in the lungs, were examined. The TNF‐α transgenic mouse is an animal model of human idiopathic pulmonary fibrosis which also frequently develops lung cancer. Expressions of TNF‐α and IL‐6 were inhibited in the lungs of these mice after treatment with green tea in drinking water for 4 months. In addition, judging from the results of a prospective cohort study in Saitama Prefecture, Japan, green tea helps to prevent cardiovascular disease. In this study, a decreased relative risk of death from cardiovascular disease was found for people consuming over 10 cups of green tea a day, and green tea also had life‐prolonging effects on cumulative survival. These data suggest that green tea has preventive effects on both chronic inflammatory diseases and lifestyle‐related diseases (including cardiovascular disease and cancer), resulting in prolongation of life span.
Hypoxia-inducible factor-1alpha (HIF-1 alpha) plays an essential role in the regulation of various genes associated with low oxygen consumption. Elevated expression of HIF-1alpha has been reported to ...be associated with tumor progression, invasion and metastasis in many cancers. To investigate the role of HIF-1alpha in tumor development and metastasis, we established transgenic mice constitutively expressing HIF1A gene under regulation of the cytomegalovirus gene promoter. Although HIF-1alpha protein levels varied among organs, expression of HIF1A mRNA in most organs gradually increased in an age-dependent manner. The transgenic mice showed no gross morphological abnormality up to 8 weeks after birth, although they subsequently developed tumors in the lymphoid, lung, and breast; the most prominent tumor was lymphoma appearing in the intestinal mucosa and intra-mesenchymal tissues. The prevalence of tumors reached 80% in 13 months after birth. The constitution of lymphocyte populations in the transgenic mice did not differ from that in wild-type mice. However, lymphocytes of the transgenic mice revealed prolonged survival under long-term culture conditions and revealed increased resistance to cytotoxic etoposide. These results suggest that HIF-1alpha itself is not oncogenic but it may play an important role in lymphomagenesis mediated through the prolonged survival of lymphocytes in this transgenic mouse model.
A member of the family of p53‐related genes, p63 plays a role in regulating epithelial proliferation and differentiation programs, but the pathological and clinical meaning of p63 in B‐cell lymphoma ...has not been elucidated. We investigated the expression pattern of p63 in B‐cell malignancies, and evaluated the correlation between the expression of p63 and other germinal center markers. Ninety‐eight B‐cell lymphomas (28 FCL, 5 MCL, and 65 DLBCL) were analyzed by immunohistochemical examination for p63, bcl‐6, CD10 and MUM‐1 proteins, and for rearrangement of bcl‐2/IgH. Expression of p63 was observed in the nuclei of tumor cells obtained from 15 of 28 (54%) FCL, 22 of 65 (34%) DLBCL, but none of 5 MCL. In DLBCL, the expression of p63 and bcl‐6 showed a significant correlation (P < 0.02), but no correlation was observed between p63 and expression of CD10, MUM‐1, or bcl‐2/IgH rearrangement. RT‐PCR revealed that TAp63α‐type transcripts, a possible negative regulator of transcriptional activation of p21 promoter, were major transcripts in B‐cell lymphoma tissues. As for prognostic significance, only patients in the p63 positive group of FCL died, and in the non‐germinal center group, the p63 positive cases appeared to have inferior overall survival than other groups in DLBCL. Our preliminary results suggested that p63 expression is a disadvantageous factor for prognosis in this subgroup of B‐cell lymphomas. (Cancer Sci 2006; 97: 1050–1055)
Although the anti-CCR4 antibody mogamulizumab (moga) shows striking antitumor activity against adult T cell leukemia (ATL), it can also cause fatal immunological pathology such as severe skin rash ...and graft-versus-host disease, which might be attributed to depletion of CCR4
regulatory T cells. We previously showed that next generation sequencing enables precise analysis of the T cell receptor (TCR) repertoire, and we here used the technique to reveal the immunological dynamics in moga-treated ATL patients. Treatment with moga resulted in remarkable reduction or elimination of clonal cells, and enhanced reconstitution of non-tumor polyclonal CD4
T cells and oligoclonal CD8
T cells. Interestingly, cutaneous T cells infiltrating moga-related skin rashes did not share the same major clones in peripheral blood, which minimizes the possibility of cross-reaction. Thus, deep sequencing of the TCR can reveal the immune reconstitution of moga-treated ATL and provides powerful insights into its mode of action.
Epidermal growth factor receptor (EGFR) mutations in lung cancer enhance tyrosine kinase activity and increase sensitivity to the EGFR tyrosine kinase inhibitor, gefitinib. Mutation analysis of the ...EGFR gene is therefore indispensable for predicting gefitinib response. We investigated a CA‐repeat polymorphism in the EGFR gene related to EGFR mutations. Because an increasing number of CA‐repeats at intron 1 of the EGFR gene has been reported to reduce transcription activity, we examined the relationship between EGFR mutations and this CA‐repeat polymorphism. EGFR mutations at exon 19 were closely associated with shorter CA‐repeat length in the shorter allele, but this was not the case for EGFR mutations at exons 18 or 21. Increased intrinsic EGFR mRNA expression in non‐cancerous lung tissues from lung adenocarcinoma patients was also significantly associated with shorter CA‐repeat length. A higher frequency of EGFR mutations at exon 19 was associated with shorter CA‐repeat length only in patients with high levels of EGFR mRNA expression. To determine the phenotypes of cells possessing shorter CA‐repeats, an in vitro study using human bronchial epithelial cells with different CA‐repeat lengths was performed; more rapid cell growth and activated EGF/EGFR signaling were found more often in the cells having both shorter CA‐repeats and increased EGFR mRNA expression. These results suggest that CA‐repeat length in the EGFR gene may be a genetic factor related to cancer in the case of EGFR mutations at exon 19. The mechanism likely involves enhanced intrinsic expression of EGFR mRNA and activated EGF/EGFR signaling that accompany shorter CA‐repeats. (Cancer Sci 2008; 99: 1180–1187)
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