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Kunihiro Tsukasaki

Publications and source records attributed to Kunihiro Tsukasaki.

At least 19 recordsLinked to original sources
PubMed2007

Expression of CCR9 in HTLV-1+ T cells and ATL cells expressing Tax.

Adult T-cell leukemia (ATL) is a highly aggressive mature CD4+ T-cell malignancy that is etiologically associated with human T-lymphotropic virus Type 1 (HTLV-1). ATL is characterized by frequent infiltration of lymph nodes, spleen, liver, skin and gut. Previously, we and others have shown that the majority of ATL cases are strongly positive for CCR4, which may explain the frequent skin invasion of ATL. Here, we examined whether ATL cells express CCR9, which is involved in T-cell homing to the gastrointestinal tract. Human T cell lines carrying HTLV-1 consistently expressed CCR9 together with the HTLV-1-encoded transcriptional activator Tax. Although ATL cells freshly isolated from peripheral blood hardly expressed CCR9, ATL cells cultured for 1 day consistently expressed CCR9 in parallel with the upregulation of Tax. Induction of Tax by Cd2+ in JPX-9, a subline of Jurkat human T cell line carrying Tax under the control of metallothionein promoter, led to upregulation of CCR9. A luciferase reporter gene under the control of the CCR9 promoter was expressed by cotransfection of an expression vector for Tax or in Cd2+-treated JPX-9 cells. Furthermore, immunohistochemical staining demonstrated that ATL cells infiltrating gastrointestinal tract were frequently positive for CCR9. Collectively, CCR9 is inducible in ATL cells expressing Tax and may play a role in the gastrointestinal involvement of ATL.

Adult↗
PubMed2006

Impact of visceral involvements and blood cell count abnormalities on survival in adult T-cell leukemia/lymphoma (ATLL).

Multiple visceral involvements and various blood cell count abnormalities are frequently manifested in adult T-cell leukemia/lymphoma (ATLL) at diagnosis. We evaluated the effects of four visceral involvement (bone marrow (BM), skin, liver, spleen) and six blood cell count abnormalities (anemia, neutrophilia, thrombocytopenia, monocytosis, eosinophilia, basophilia) on the overall survival of 168 ATLL patients. In the aggressive type, BM involvement, skin involvement and monocytosis were significantly poor prognostic factors. Furthermore, concomitant involvement of BM and additional visceral organs worsened the prognosis. These data support that multiple organ involvements represent a poor prognostic factor for ATLL and provide clinical significance for BM examinations.

Adult↗
PubMed2006

Impact of p53 aberration on the progression of Adult T-cell Leukemia/Lymphoma.

Based on statistical analysis of its age-dependent occurrence, a multi-step carcinogenesis model has been proposed for Adult T-cell Leukemia/Lymphoma (ATLL). We have previously reported that the deletion of the p16 gene is a key event in ATLL progression. In the current study, we report for the first time that the aberrations of p16 and p53 are mutually exclusive in ATLL and either of the two events is sufficient for the ATLL progression. More than half of the patients had one of the two aberrations, and both aberrations emerged as significant markers for a poor prognosis.

Adult↗
PubMed2006

Comparative genomic hybridization analysis of Japanese B-cell chronic lymphocytic leukemia: correlation with clinical course.

B-cell chronic lymphocytic leukemia (B-CLL) is the most common leukemia in Westerners. By contrast, B-CLL is rare in Asians, including Japanese. We applied comparative genomic hybridization (CGH) to screen 26 newly diagnosed Japanese B-CLL patients for genomic aberrations. Chromosomal imbalances were detected in 12 of the 26 cases (46%). The most frequent changes observed were gains of chromosomes 3q in five cases (19%) and 17q in three cases (12%). Other recurrent imbalances included gains of chromosomes 8q, 18q and losses of chromosomes 13q and 17p. Samples obtained at different sites disclosed identical CGH findings in all of the three cases examined. Genomic imbalances as detected by CGH were associated with disease progression and shorter survival. Two patients, with chromosomal imbalances, including gains of both 3q and 18q, developed large cell transformation of the disease within 4 years. In conclusion, CGH abnormality was associated with poor prognosis in Japanese B-CLL, and features of Japanese B-CLL, compared to chromosomal abnormalities of Western B-CLL in the literature, include a lower incidence of any abnormality in particular regarding gain of 12q, with the exception of a higher incidence of gains at 3q.

Adult↗
PubMed2006

Survey of chemokine receptor expression reveals frequent co-expression of skin-homing CCR4 and CCR10 in adult T-cell leukemia/lymphoma.

Adult T-cell leukemia/lymphoma (ATLL) is a malignancy of mature T-cell origin with multi-organ involvement. Because the chemokine receptors play crucial roles in tissue-specific homing of mature lymphocytes, particular chemokine receptors expressed on ATLL cells may be involved in their tissue infiltration. We thus performed a comprehensive survey on the chemokine receptor expression in ATLL. ATLL cells expressed transcripts of CCR1, CCR4, CCR7, CCR8, CCR10 and CXCR4 but hardly expressed those of CCR2, CCR3, CCR5, CCR6, CCR9, CXCR1, CXCR2, CXCR3 and CXCR5. These results were confirmed at the protein level by flow cytometric analysis. Notably, patients who have skin lesions showed significantly higher levels of CCR10 mRNA expression than patients without skin lesions. ATLL cells migrated efficiently to the CCR4 ligand, CCL22, and moderately to the CCR10 ligands, CCL27 and CCL28. Moreover, ATLL skin lesions consistently contained transcripts of CCR10 and its ligands CCL27 and CCL28 besides those of CCR4 and its ligands CCL17 and CCL22 that have been reported previously. Collectively, the frequent co-expression of CCR4 and CCR10, the known pair of skin-homing chemokine receptors, may play an important role in ATLL invasion into the skin.

Chemokines↗
PubMed2006

[Plasmodium vivax malaria with clinical presentation mimicking acute type idiopathic thrombocytopenic purpura].

Causes of thrombocytopenia are diverse, and infection with plasmodia often brings about thrombocytopenia. Japan is not an endemic area of malaria infection at present and most cases are travelers to endemic areas. In some cases, initial clinical diagnoses may not be correct because of a variety of symptoms, physical findings and laboratory abnormalities. A 67-year-old female, who had traveled to South American countries 2 months before the onset of the disease, presented with a case of vivax malaria. Because of the patient's high fever, profound thrombocytopenia (1.5 x 10(4)/microl), and elevated platelet-associated IgG on admission, our initial diagnosis was acute type idiopathic thrombocytopenic purpura (ITP). However, we recognized her tertian fever and plasmodial vivax in erythrocytes 4 days later. She responded promptly to anti-parasitic therapy after diagnosis of malaria and her laboratory data also improved. Travel history is indicative of malaria infection in some cases with thrombocytopenia mimicking acute ITP.

Acute Disease↗
PubMed2005

Chromosomal aberrations in follicular non-Hodgkin lymphomas of Japanese patients, detected with comparative genomic hybridization and polymerase chain reaction analysis.

The t(14;18)(q32.3;q21), hallmark of follicular lymphoma (FL), is less frequently observed in Asian patients than in Westerners. Little is known about additional chromosomal aberrations in Asian FL patients. We applied comparative genomic hybridization (CGH) to screen for genomic imbalances in 32 biopsy samples from 23 Japanese patients with nodal FL. The t(14;18) was assessed with polymerase chain reaction (PCR) using primers for the major (MBR), 3'MBR, minor (mcr), 5'mcr, and intermediate breakpoint cluster regions (icr). In 17 of 23 patients, CGH analyses detected genomic imbalances. Gains frequently affected chromosomes 18p (6 of 23), X (5 of 23), 5 (4 of 23), 12 (4 of 23), 2 (3 of 23), and 16 (3 of 23). The only recurrent loss affected chromosome 6q (2 of 23). A t(14;18) was detected in 13 of 23 patients (56.5%). Breakpoints were located in the MBR (10 patients), in the 3'MBR, in the mcr, and in the icr (1 patient each). The frequency of aberrations detected by CGH as well as relapse-free survival were not distinctly different between patients with and without a t(14;18). In summary, no significant difference in the overall frequency of aberrations compared with Westerners was found. Despite the extended primer set used, the frequency of PCR-detected t(14;18) remained low. Additional studies are required to assess the reasons for geographic variation in FL.

Adult↗
PubMed2005

Dihydroflavonol BB-1, an extract of natural plant Blumea balsamifera, abrogates TRAIL resistance in leukemia cells.

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) induces apoptosis in many transformed cells but not in normal cells and, hence, has emerged as a novel anticancer agent. Previously, we showed that although most adult T-cell leukemia/lymphoma (ATLL) cells express the TRAIL death receptor DR4 (TRAIL-R1) or DR5 (TRAIL-R2), they are resistant to TRAIL. Thus, in this study, we tried to find natural products that can overcome TRAIL resistance. Among more than 150 materials screened, a dihydroflavonol that was extracted from Blumea balsamifera (BB-1) exhibited the most striking synergism with TRAIL. Treatment of the TRAIL-resistant ATLL cell line KOB, with a combination of BB-1 and TRAIL, resulted in apparent apoptosis that was not observed on treatment with either agent alone. Furthermore, pretreatment with BB-1 followed by TRAIL further augmented the synergism. BB-1 increased the level of TRAIL-R2 promoter activity and surface protein expression in a p53-independent manner. TRAIL-R2 siRNA inhibited the synergism, indicating that sensitization was caused by the increase of TRAIL-R2 expression. More interestingly, similar effects were observed in other leukemia cell lines by exactly the same mechanisms. These results suggest that combined treatment with BB-1 and TRAIL may be a new strategy for cancer therapy.

Antineoplastic Agents↗
PubMed2005

Efficient intervention of growth and infiltration of primary adult T-cell leukemia cells by an HIV protease inhibitor, ritonavir.

Adult T-cell leukemia (ATL), an aggressive malignancy of CD4+ T cells associated with human T-cell leukemia virus type I (HTLV-I) infection, carries a very poor prognosis because of the resistance of leukemic cells to any conventional regimen, including chemotherapy. We examined the effect of ritonavir, an HIV protease inhibitor, on HTLV-I-infected T-cell lines and primary ATL cells and found that it induced apoptosis and inhibited transcriptional activation of NF-kappaB in these cells. Furthermore, ritonavir inhibited expression of Bcl-xL, survivin, c-Myc, and cyclin D2, the targets of NF-kappaB. In nonobese diabetic/severe combined immunodeficient (NOD/SCID)/gammacnull (NOG) mice, ritonavir very efficiently prevented tumor growth and leukemic infiltration in various organs of NOG mice at the same dose used for treatment of patients with AIDS. Our data indicate that ritonavir has potent anti-NF-kappaB and antitumor effects and might be clinically applicable for treatment of ATL. These results would provide a new concept and novel platform for new drug development of leukemia and solid cancer as well.

Adult↗
PubMed2005

Methylation analysis of the adenomatous polyposis coli (APC) gene in adult T-cell leukemia/lymphoma.

We investigated methylation status of the adenomatous polyposis coli (APC) gene in adult T-cell leukemia/lymphoma (ATL). APC methylation was found in 15 of 31 (48%) primary samples, and 2 of 4 (50%) ATL cell lines. Methylation of the APC gene occurred more frequently in acute ATL (12/21) (57%) than chronic ATL (1/8) (13%) (P = 0.03). APC was not expressed in the APC-methylated ATL cell line ST1. Demethylation with 5-azacytidine treatment restored APC expression in the ST1 cell line. Our data show that hypermethylation of the APC gene is involved in the pathogenesis of ATL.

Adenomatous Polyposis Coli Protein↗
PubMed2005

A novel plasmacytoid dendritic cell line, CAL-1, established from a patient with blastic natural killer cell lymphoma.

Blastic natural killer (NK) cell lymphoma corresponding to CD4+CD56+ malignancies is a novel disease entity, according to the results of clinical, morphologic, and immunologic studies. It is especially noteworthy that this disease likely arises from plasmacytoid dendritic cells (pDCs), described previously as plasmacytoid T-cells, which have an important role in innate and adaptive immunity. However, the exact relationship between the tumor cells and pDCs remains to be elucidated. We encountered a patient with typical blastic NK cell lymphoma, which later converted to leukemic manifestations, and tried to establish a cell line using the leukemic cells. We succeeded in establishment of a novel cell line, CAL-1, which originated from the primary malignant cells. The genetic and phenotypic features of CAL-1 cells bear a similarity to those of pDCs, namely, plasmacytoid morphology at light and electron microscopy; negative results for CD11c and lineage-associated markers of CD3, CD14, CD19, and CD16; positive results for HLA-DR, CD4, CD56, CD45RA, and CD123; and negative results for TCR and IgH gene rearrangements. An interesting finding was that CAL-1 cells change morphologically into the mature DC appearance with many long dendrites after short-term culture in the presence of granulocyte-macrophage colony-stimulating factor and interleukin 3. CAL-1 cells can secrete tumor necrosis factor alpha but not interferon alpha. Thus although they do not share in part phenotypic and functional features with their normal counterparts, CAL-1 cells mostly exhibit a striking pDC phenotype. We describe the first novel pDC cell line of CAL-1. This cell line should open the opportunity for study not only of CD4+CD56+ tumor cells but also of pDCs in vitro.

Aged↗
PubMed2005

An ATL cell line with an IgH pseudo-rearranged band pattern by southern blotting: a pitfall of genetic diagnosis.

Adult T-cell leukemia (ATL), which is a mature T-cell malignancy that develops from human T-cell leukemia virus type-1 (HTLV-1)-infected T-cells, is diagnosed based on morphologic, immunophenotypic, serologic, and genetic characteristics. In particular, Southern blot hybridization (SBH) and polymerase chain reaction analyses for antigen receptor genes and the retrovirus of HTLV-1 provide a diagnostic hallmark for the clonality of leukemic cells and the causative agent of the disease. We report here a case of an ATL cell line, designated as SO4 cells, established from primary ATL cells presenting with an irrational genetic abnormality of the immunoglobulin heavy chain (IgH)-rearranged band in spite of harboring a clonally rearranged T-cell receptor gene and a clonally integrated provirus of HTLV-1 within their genomic DNA. Moreover, fluorescence in situ hybridization analysis using the IgH (14q32) dual-color break-apart probe revealed 3 pair-signals of colocalizing red and green spots, implying 2 intact and 1 amplified 14q32 regions without translocation, where the region contains the IgH gene locus. Although the exact mechanism remains to be elucidated, some alteration of a portion of the amplified 14q32 region seems to have a role in the false-positive band pattern in the SBH. The SO4 cells, in the hematology laboratory, will provide a lesson about the pitfalls of genetic tests for mature T-cell neoplasms and contribute to the genetic elucidation of leukomogenesis as an in vitro model.

Adult↗
PubMed2005

Methylation of the MLH1 gene in hematological malignancies.

Hypermethylation of the MLH1 gene has been described in many kinds of human cancers with microsatellite instability (MSI). However, it is not clear whether the same mechanism occurs in hematological malignancies. Genomic DNA was extracted from 31 patients with adult T-cell leukemia/lymphoma (ATL), 9 patients with acute lymphoblastic leukemia (ALL) who had MSI, and 12 leukemia and lymphoma cell lines with MSI. Aberrant methylation of the MLH1 gene was found in 2/31 (6%) ATL patients, and in 1/12 (8%) cell lines with MSI. MLH1 promoter was not methylated in either of the twelve peripheral blood samples from normal individuals or ALL samples. The MLH1 gene was expressed in the normal peripheral blood samples, but not in the MLH1-methylated cell line KCL22. Demethylation with 5-Azacytidine treatment restored MLH1 expression in the KCL22 cell line. Methylation of the MSH2 gene was not found in any of the samples. Our data show that hypermethylation of the MLH1 gene is occasionally involved in the pathogenesis of hematological malignancies, but is not always associated with MSI.

Adaptor Proteins, Signal Transducing↗
PubMed2004

Identifying progression-associated genes in adult T-cell leukemia/lymphoma by using oligonucleotide microarrays.

Adult T-cell leukemia/lymphoma (ATL) is associated with human T-lymphotropic virus type-1 (HTLV-1). To understand the changes in expression that occur in the progression of chronic phase of ATL to acute crisis, the gene expression profiles of fresh ATL cells were compared in 4 pairs of samples (progression of chronic to acute phase in 3 patients, as well as 1 typical chronic phase sample vs. 1 typical acute phase sample) using high-density oligonucleotide DNA arrays. We identified 203 genes that were commonly upregulated in acute vs. chronic phase samples including ribosomal proteins, proteosome subunits, eukaryotic translation factors, immunophilins, heat shock proteins and genes important for DNA replication. Additionally, we identified 91 commonly downregulated genes including immune molecules related to MHC and a phosphatase. Several of the genes were previously identified to be associated with the Tax protein of HTLV-1. Some of the upregulated genes were located in amplified regions identified by comparative genomic hybridization in the corresponding chronic/acute ATL sample. Using real-time quantitative PCR, we confirmed the array-results in those specimens analyzed by microarray. These results demonstrated that distinct sets of genes that are known to be critical in cellular transformation and/or activation are up- or down-regulated during the transition to the acute phase of ATL.

Biomarkers, Tumor↗
PubMed2004

Methylenetetrahydrofolate reductase genotype does not play a role in adult T-cell leukemia/lymphoma pathogenesis among human T-lymphotrophic virus type 1 carriers.

Human T-lymphotropic virus type 1 (HTLV-1) is associated with adult T-cell leukemia/lymphoma (ATL). However, the incidence of ATL is low among HTLV-1 carriers suggesting additional mechanisms are involved in the progression of the disease. A recent study found that polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene influence the susceptibility to malignant lymphoma. We have analyzed the MTHFR genotype in 81 HTLV-1 carriers and 87 ATL patients. No statistically significant associations were found between MTHFR genotype and development of ATL. These data suggest that genetic polymorphisms in the MTHFR locus do not play a role in ATL pathogenesis among HTLV-1 carriers.

Carrier State↗
PubMed2004

Apoptosis induced by the histone deacetylase inhibitor FR901228 in human T-cell leukemia virus type 1-infected T-cell lines and primary adult T-cell leukemia cells.

Inhibition of histone deacetylase (HDAC) activity induces growth arrest, differentiation, and, in certain cell types, apoptosis. FR901228, FK228, or depsipeptide, is an HDAC inhibitor effective in T-cell lymphomas. Adult T-cell leukemia (ATL) is caused by human T-cell leukemia virus type 1 (HTLV-1) and remains incurable. We examined whether FR901228 is effective for treatment of ATL by assessing its ability to induce apoptosis of HTLV-1-infected T-cell lines and primary leukemic cells from ATL patients. FR901228 induced apoptosis of Tax-expressing and -unexpressing HTLV-1-infected T-cell lines and selective apoptosis of primary ATL cells, especially those of patients with acute ATL. FR901228 also efficiently reduced the DNA binding of NF-kappaB and AP-1 in HTLV-1-infected T-cell lines and primary ATL cells and down-regulated the expression of Bcl-x(L) and cyclin D2, regulated by NF-kappaB. Although the viral protein Tax is an activator of NF-kappaB and AP-1, FR901228-induced apoptosis was not associated with reduced expression of Tax. In vivo use of FR901228 partly inhibited the growth of tumors of HTLV-1-infected T cells transplanted subcutaneously in SCID mice. Our results indicated that FR901228 could induce apoptosis of these cells and suppress the expression of NF-kappaB and AP-1 and suggest that FR901228 could be therapeutically effective in ATL.

Adult↗