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Biomedical subjects

Masao Tomonaga

Publications and source records attributed to Masao Tomonaga.

At least 19 recordsLinked to original sources
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

Expression of the myeloperoxidase gene in AC133 positive leukemia cells relates to the prognosis of acute myeloid leukemia.

We previously reported that the percentage of myeloperoxidase (MPO) positive blasts had a prognostic impact on survival of patients with acute myeloid leukemia (AML). To extend this observation, we quantitatively measured the level of the MPO gene in AC133 positive leukemia cells that would contain a putative AML stem/progenitor compartment. AML cases were divided into the MPO gene high (MPOg-H) and MPO gene low (MPOg-L) groups. Only patients belonging to the MPOg-H group had a favorable chromosomal translocation, t(8;21), and having no morphological dysplasia that was associated with MPOg-L. The difference in the survival of MPOg-H and MPOg-L was statistically meaningful, demonstrating the possible prognostic impact of the expression of MPO gene in AC133 positive leukemia cells.

AC133 Antigen↗
PubMed2006

Chemokine expression in human erythroid leukemia cell line AS-E2: macrophage inflammatory protein-3alpha/CCL20 is induced by inflammatory cytokines.

OBJECTIVE: Normal and malignant hematopoietic cells are shown to express and secrete various cytokines and chemokines, some of which are believed to play an important role in normal and abnormal hematopoiesis in an autocrine/paracrine manner. To explore the possibility of a cytokine/chemokine network participating in the pathophysiology of anemic disorders, we evaluated the ability of inflammatory cytokines to induce chemokine expression using erythroid progenitor cells. METHODS: Erythropoietin-dependent human leukemia cell line AS-E2 was used as a model of erythroid colony-forming unit (CFU-E) cells. The expression of mRNA of 8 chemokines was examined using RT-PCR, before and after TNF-alpha, IFN-gamma, and IL-1beta stimulation. For MIP-3alpha, the promoter activity was analyzed by luciferase assay and secretion was confirmed by ELISA. The expression of CCR6, the specific receptor for MIP-3alpha, was analyzed by RT-PCR and flow cytometry. RESULTS: Unstimulated AS-E2 cells constitutively expressed transcripts for MCP-4, IP-10, PF-4, IL-8, and MIP-3alpha. Stimulation with TNF-alpha, IFN-gamma, and IL-1beta upregulated MIP-3alpha mRNA expression and induced its protein secretion. Luciferase assay revealed that these cytokines could upregulate promoter activity of the MIP-3alpha gene, possibly through the NF-kappaB pathway. CCR6 mRNA was detected and its intracellular expression was confirmed. CONCLUSION: These data suggest that inflammatory cytokine-stimulated erythroid progenitors secrete MIP-3alpha, which may function in an autocrine/paracrine manner. Furthermore, the existence of intracellular CCR6 suggests the involvement in cytokine signaling of a MIP-3alpha-dependent internal autocrine mechanism. These mechanisms may play a role in pathophysiology of anemic disorders, such as secondary anemia and bone marrow failure syndromes.

Cell Line, Tumor↗
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

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

Difference in clinical features between Japanese and German patients with refractory anemia in myelodysplastic syndromes.

Several reports indicate that there might be differences in clinical features between Asian and Western myelodysplastic syndrome (MDS) cases. We analyzed refractory anemia (RA) in French-American-British (FAB) classification cases diagnosed in Japan and Germany to perform a more exact comparison between Asian and Western MDS types. In the first step, we analyzed agreement of morphologic diagnosis between Japanese and German hematologists. Blood and bone marrow slides of 129 patients diagnosed with FAB-RA, FAB-RA with ringed sideroblasts (RARS), or aplastic anemia were selected randomly and evaluated separately by each group. The agreements of diagnoses according to FAB and World Health Organization (WHO) classifications were 98.4% and 83.8%, respectively. Second, we compared clinical features between 131 Japanese and 597 German patients with FAB-RA. Japanese patients were significantly younger than German patients. Japanese patients had more severe cytopenias. However, prognosis of Japanese patients was significantly more favorable than that of German patients. Japanese patients had a significantly lower cumulative risk of acute leukemia evolution than did German patients. Frequency of WHO-RA in Japanese patients with FAB-RA was significantly higher than that in German patients. In conclusion, our results indicate that the clinical features of Japanese patients with FAB-RA differ from those of German patients.

Acute Disease↗
PubMed2005

Potential immunogenicity of adult T cell leukemia cells in vivo.

Experimental vaccines targeting human T cell leukemia virus type-I (HTLV-I) Tax have been demonstrated in a rat model of HTLV-I-induced lymphomas. However, the scarcity of HTLV-I-expression and the presence of defective HTLV-I-proviruses in adult T cell leukemia (ATL) cells have raised controversy about the therapeutic potential of HTLV-I-targeted immunotherapy in humans. We investigated the expression of HTLV-I antigens in fresh ATL cells by using both in vitro and in vivo assays. In flow cytometric analysis, we found that 3 of 5 acute-type and six of fifteen chronic-type ATL patients tested showed significant induction of HTLV-I Tax and Gag in their ATL cells in a 1-day culture. Concomitantly with HTLV-I-expression, these ATL cells expressed co-stimulatory molecules such as CD80, CD86 and OX40, and showed elevated levels of antigenicity against allogeneic T cells and HTLV-I Tax-specific cytotoxic T-lymphocytes (CTL). Representative CTL epitopes restricted by HLA-A2 or A24 were conserved in 4 of 5 acute-type ATL patients tested. Furthermore, spleen T cells from rats, which had been subcutaneously inoculated with formalin-fixed uncultured ATL cells, exhibited a strong interferon gamma-producing helper T cell responses specific for HTLV-I Tax-expressing cells. Our study indicated that ATL cells from about half the patients tested readily express HTLV-I antigens including Tax in vitro, and that ATL cells express sufficient amounts of Tax or Tax-induced antigens to evoke specific T cell responses in vivo.

Adult↗
PubMed2005

Allogeneic stem-cell transplantation with reduced conditioning intensity as a novel immunotherapy and antiviral therapy for adult T-cell leukemia/lymphoma.

Sixteen patients with adult T-cell leukemia/lymphoma (ATL) who were all over 50 years of age underwent allogeneic stem cell transplantation with reduced-conditioning intensity (RIST) from HLA-matched sibling donors after a conditioning regimen consisting of fludarabine (180 mg/m2), busulfan (8 mg/kg), and rabbit antithymocyte globulin (5 mg/kg). The observed regimen-related toxicities and nonhematologic toxicities were all found to be acceptable. Disease relapse was the main cause of treatment failure. Three patients who had a relapse subsequently responded to a rapid discontinuation of the immunosuppressive agent and thereafter achieved another remission. After RIST, the human T-cell leukemia virus type 1 (HTLV-1) proviral load became undetectable in 8 patients. RIST is thus considered to be a feasible treatment for ATL. Our data also suggest the presence of a possible graft-versus-ATL effect; an anti-HTLV-1 activity was also found to be associated with this procedure.

Aged↗
PubMed2005

Correlation of donor-derived keratinocytes and severity of graft-versus-host disease (GVHD) in epidermis.

Recent reports suggest that bone marrow might serve as a source of skin progenitor cells. Graft-versus-host disease (GVHD) is a systemic disease that involves the skin, the liver, and the gastrointestinal tract, and contributes to transplant-related morbidity and mortality. To evaluate whether donor-derived bone marrow cells participated in its pathophysiology, we correlated the severity of GVHD in skin from sex-mismatched recipients with the percentage of donor-derived keratinocytes using fluorescence in situ hybridization (FISH) for detecting the Y chromosome. Y-positive signals were observed in female epidermis in both keratinocytes and lymphocytes. These results support the notion that donor-derived hematopoietic stem cells may contain pluripotent stem cells. Furthermore, there was a strong correlation between the frequency of Y-positive keratinocytes and the histopathologic grade of GVHD (p = 0.004), as well as with the number of Y-positive lymphocytes infiltrating the epidermis (p = 0.005), suggesting a role for donor-derived keratinocytes in the pathophysiology of GVHD. However, no clusters of Y-positive keratinocytes were found in the epidermis, and no correlation was observed between the number of Y-positive keratinocytes and time course of GVHD after transplantation. We hypothesize that donor-derived stem cells may play a role in the regeneration of damaged keratinocytes in GVHD.

Adult↗
PubMed2005

Tumor immunity against adult T-cell leukemia.

Human T-cell leukemia virus type-I (HTLV-I) causes adult T-cell leukemia (ATL) in a small population of infected individuals after a long incubation period. Although the process of clonal evolution of ATL cells may involve multiple steps, ATL cells from half of the ATL cases still retain the ability to express HTLV-I Tax, a key molecule of HTLV-I leukemogenesis. A recent finding of reactivation of Tax-specific cytotoxic T lymphocytes (CTL) in ATL patients after hematopoietic stem cell transplantation suggests the presence of Tax expression in vivo and potential contribution of the CTL to antitumor immunity. This is consistent with the results of a series of animal experiments indicating that Tax-specific CTL limit the growth of HTLV-I-infected cells in vivo, although the animal model mimics only an early phase of HTLV-I infection and leukemogenesis. Establishment of an insufficient HTLV-I-specific T-cell response and an increased viral load in orally HTLV-I-infected rats suggests that host HTLV-I-specific T-cell response at a primary HTLV-I infection can be a critical determinant of persistent HTLV-I levels thereafter. These findings indicate that Tax-targeted vaccines may be effective for prophylaxis of ATL in a high-risk group, and also for therapy of ATL in at least half the cases.

Animals↗
PubMed2005

Possible origin of adult T-cell leukemia/lymphoma cells from human T lymphotropic virus type-1-infected regulatory T cells.

Adult T-cell leukemia/lymphoma (ATLL) is a lymphoproliferative disorder caused by human T lymphotropic virus type 1 (HTLV-I). Although ATLL cells display an activated helper/inducer T-cell phenotype, CD4+ and CD25+, they are known to exhibit strong immunosuppressive activity. As regulatory T cells (Treg cells) express CD4+ and CD25+ molecules and possess potent immune response suppressive activity, we investigated a possible link between ATLL cells and Treg cells. In primary ATLL cells, the expression levels of the Treg cell marker molecules Foxp3 and glucocorticoid-induced tumor necrosis factor receptor family related protein (GITR) were significantly higher than in those from healthy adults. Furthermore, ATLL cells are unresponsive in vitro to concanavalin A stimulation and suppress the proliferation of normal T cells. GITR mRNA expression was induced by the HTLV-I transactivator Tax, and GITR promoter analyses revealed that this induction depends on the kappaB site from -431 bp to -444 bp upstream of the putative transcription site. Taken together, ATLL cells may originate from HTLV-I-infected Treg cells, and GITR seems to be involved in the progression to ATLL.

Adult↗
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↗