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ABSTRACT: A lineage switch in leukemia, in which the leukemic cell lineage at onset converts to another lineage at a later time, is an uncommon type of hybrid (mixed) leukemia regarded as a variation of bilineage leukemia. We present a case of a 60-year-old female diagnosed with precursor B cell acute lymphoblastic leukemia (ALL), whose markers in flow cytometry shifted from their original status of CD19+, 22+, 79a+, 13+, HLA-DR+, and TdT+. Although her bone marrow achieved remission after induction therapy, there was a small residual population of leukemic cells in the liver. Residual disease was proved by biopsy and pathologically shown to have an immature phenotype of CD5+, CD10-, CD20-, CD79a- and myeloperoxidase negativity. Two weeks after liver biopsy, blast cells progressively appeared in the peripheral blood; these cells had a monocytoid morphology and phenotype (CD13, 14) but were accompanied by myeloid (CD33) and lymphoid (CD2, 4, 20) cells. Markers CD7, 10 and 19 were negative by flow cytometry. This phenotypical conversion from B-ALL to hybrid leukemia featuring monocytoid characteristics is known as a lineage switch. This case suggests that leukemic subclones tend to carry out dedifferentiation, occasionally in extramedullary sites, which serve as a hotbed for the selection of resistant clones.
International Journal of Clinical Oncology 02/2010; 15(1):112-5. · 1.41 Impact Factor
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ABSTRACT: The Tec protein tyrosine kinase (PTK) belongs to a group of structurally related nonreceptor PTKs that also includes Btk, Itk, Rlk, and Bmx. Previous studies have suggested that these kinases play important roles in hematopoiesis and in the lymphocyte signaling pathway. Despite evidence suggesting the involvement of Tec in the T-lymphocyte activation pathway via T-cell receptor (TCR) and CD28, Tec's role in T-lymphocytes remains unclear because of the lack of apparent defects in T-lymphocyte function in Tec-deficient mice. In this study, we investigated the role of Tec in human T-lymphocyte using the Jurkat T-lymphoid cell line stably transfected with a cDNA encoding Tec. We found that the expression of wild-type Tec inhibited the expression of CD25 induced by TCR cross-linking. Second, we observed that LFM-A13, a selective inhibitor of Tec family PTK, rescued the suppression of TCR-induced CD25 expression observed in wild-type Tec-expressing Jurkat cells. In addition, expression of kinase-deleted Tec did not alter the expression level of CD25 after TCR ligation. We conclude that Tec PTK mediates signals that negatively regulate CD25 expression induced by TCR cross-linking. This, in turn, implies that this PTK plays a role in the attenuation of IL-2 activity in human T-lymphocytes.
Immunology letters 10/2009; 127(2):135-42. · 2.91 Impact Factor
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ABSTRACT: In this study, we examined the biological functions of Gab1 in erythropoietin receptor (EPOR)-mediated signaling in vivo. Knockdown of Gab1 by the introduction of the Gab1 siRNA expression vector into F-36P human erythroleukemia (F-36P-Gab1-siRNA) cells resulted in a reduction of cell proliferation and survival in response to EPO. EPO-induced activation of Erk1/2 but not of Akt was significantly suppressed in F-36P-Gab1-siRNA cells compared with mock-transfected F-36P cells. The co-immunoprecipitation experiments revealed an EPO-enhanced association of Gab1 with the Grb2-SOS1 complex and SHP-2 in F-36P cells. A selective inhibitor of phosphatidylinositol 3-kinase (PI3K) LY294002 and short interfering RNA (siRNA) duplexes targeting the p85 regulatory subunit of PI3K (p85-siRNA) independently suppressed tyrosine phosphorylation of Gab1; its association with Grb2, SHP-2 and p85; and the activation of Erk in EPO-treated F-36P cells. LY294002 inhibited EPO-induced tyrosine phosphorylation of Gab1 and its association with Grb2 in human primary EPO-sensitive erythroid cells. The co-immunoprecipitation experiments using the Jak inhibitor AG490 or siRNA duplexes targeting Jak2 and in vitro binding experiments demonstrated that Jak2 regulated Gab1-mediated Erk activation through tyrosine phosphorylation of Gab1. Taken together, these results suggest that Gab1 couples PI3K-mediated EPO signals with the Ras/Erk pathway and that Gab1 plays an important role in EPOR-mediated signal transduction involved in the proliferation and survival of erythroid cells.
Cellular signalling 09/2009; 21(12):1775-83. · 4.09 Impact Factor
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International journal of hematology 11/2008; 88(4):468-70. · 1.17 Impact Factor
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ABSTRACT: Thrombotic thrombocytopenic purpura (TTP) is a rare disorder of small vessels. TTP is associated with deficiency of the von Willebrand factor-cleaving protease, ADAMTS13, and its inhibitor. Low ADAMTS13 activity is present in most of idiopathic TTP patients. The prognosis of TTP was improved by plasma exchange treatment, which replaces the ADAMTS13 and removes ADAMTS13 inhibitor. However, ADAMTS13 activity is normal in some TTP patients. These are found among the secondary TTP patients associated with collagen disease, hematopoietic stem cell transplantation, malignancy, or drugs. In addition, most of them do not respond to plasma exchange. On the other hand, several reports demonstrated that rituximab, which is an anti-CD20 monoclonal antibody, is effective for refractory TTP cases caused by ADAMTS13 deficiency. It is considered that the effect of rituximab is associated with disappearance of ADAMTS13 inhibitor. However, rituximab therapy was effective for the TTP patients with normal ADAMTS13 activity in our cases. We considered another mechanism of rituximab for TTP cases.
Clinical Rheumatology 01/2008; 26(12):2159-62. · 2.00 Impact Factor
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Noriko Manabe, Genji Yamaoka,
Hiroaki Ohnishi,
Takeshi Arai,
Hiromi Nakaishi,
Tatushi Kajikawa,
Yoshitsugu Kubota,
Terukazu Tanaka,
Akira Kitanaka,
Masato Waki,
Kimihiro Kawakami,
Masami Nagai,
Toshihiko Ishida,
Tomohiko Taminato
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ABSTRACT: CD5+ diffuse large B-cell lymphoma(CD5+DLBCL) is known to have different characteristics than CD5-DLBCL and mantle cell lymphoma(MCL). 9 patients with CD5+DLBCL were reviewed, and the results were compared with those of 8 CD5-DLBCL and 3 cyclin D1+MCL patients. CD5+DLBCL was more closely related to many aggressive clinical features or parameters than CD5-DLBCL: 67% of the patients were older than 60 years, 67% with performance status > or = 2, 89% with serum lactate dehydrogenase level higher than normal, 78% with stage III/IV disease at diagnosis, and 78% with more than one extranodal lesion. The overall International Prognostic Index score for the patients with CD5+DLBCL was thus significantly higher than that for those with CD5-DLBCL. Immunophenotypically, CD5+DLBCL was characterized by CD5+CD10-CD19+CD20+CD21-CD23-cyclin D1-phenotype and the predominant expression of surface IgM. Of particular interest is that the survival rate of CD5+DLBCL patients was significantly inferior to that of patients with CD5-DLBCL. To further characterize CD5+DLBCL, we semi-quantified the CD5 expression in DLBCL cells. Our findings suggest that CD5+DLBCL may constitute a unique subgroup of DLBCL and, moreover, CD5+DLBCL may consist of several subgroups.
Rinsho byori. The Japanese journal of clinical pathology 09/2002; 50(9):906-11.
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ABSTRACT: A novel cell line, designated OHK, was established from ascites of a 59-year-old Japanese woman with diffuse large B-cell lymphoma showing a peculiar serosal tropism, as seen in primary effusion lymphomas (PEL). OHK exhibited a large pleomorphic morphology with irregular nuclei and distinct nucleoli, and included immunoblastic and Reed-Sternberg-like giant cells. On ultrastructural examination, rich intermediate filaments, and well-developed Golgi apparati and rough endoplasmic reticulum, were seen. Immunophenotypically, OHK lacked T and B cell-associated antigens, and had CD10, CD30, CD33 and CD138 antigens. Although OHK cells did not express immunoglobulin (Ig) protein, Southern blot analysis demonstrated clonal rearrangements of Ig heavy and light chain genes. These observations suggest that OHK cells are derived from preterminally differentiated B cells, and that they have features of PEL. Kaposi's sarcoma-associated herpesvirus and Epstein-Barr virus were not detected. OHK displayed hyperploid karyotypes with multiple structural abnormalities, and produced some cytokines such as macrophage-colony-stimulating factor (M-CSF), granulocyte-CSF, interleukin 6 and transforming growth factor beta 1. In particular, vascular endothelial growth factor (VEGF), whose stimulation of vascular permeability is thought to be critical to the pathogenesis of PEL, was also produced in large quantities. These results indicate that OHK may be a useful tool for the investigation of PEL.
British Journal of Haematology 02/2002; 116(1):128-34. · 4.94 Impact Factor
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Masami Nagai,
Mitsuhiro Fujita,
TakashiI Ikeda,
Minoru Ohmori,
Hiroko Kuwabara, Genji Yamaoka,
Kimio Tanaka,
Nanao Kamada,
Masafumi Taniwaki,
Tokiko Inoue,
Shozo Irino,
Jiro Takahara
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ABSTRACT: A novel GM-CSF-dependent myeloid cell line, OHN-GM, was established from a patient who developed acute myelogenous leukaemia (AML) as a consequence of myelodysplastic syndrome (MDS). As the patient had previously received cytotoxic chemotherapy for Hodgkin's disease, the MDS and AML were probably related to such therapy. Sequential karyotypic analysis established a del(5q) as the initial cytogenetic abnormality. Additional alterations, including t(10;13)(q24;q14), had developed subsequently during disease progression. Southern blot analysis of OHN-GM cells suggested deletion of one allele of the IRF-1 gene, although no aberrant transcripts were detected. Fluorescence in situ hybridization analysis revealed the deletion of the Rb gene due to the t(10;13)(q24;q14) translocation, and Western blot analysis demonstrated the absence of Rb protein in OHN-GM cells. Finally, the OHN-GM cells exhibited two missense point mutations in highly conserved regions of the p53 gene. These observations suggest that a multistep process, involving alterations of Rb and p53 genes, may have contributed to the patient's disease development and progression. To our knowledge, OHN-GM is the first cell line derived from a therapy-related AML. These cells may aid the investigation of leukaemogenesis as well as the biology of secondary leukaemia.
British Journal of Haematology 07/1997; 98(2):392 - 398. · 4.94 Impact Factor
