Biomedical subjects

Kazuo Oshimi

Publications and source records attributed to Kazuo Oshimi.

47 records · Page 3Linked to original sources

PubMed2002

A novel chromosomal translocation t(1;14)(q25;q32) in pre-B acute lymphoblastic leukemia involves the LIM homeodomain protein gene, Lhx4.

Chromosome 1q21-25 is one of the hotspots of chromosomal abnormalities including translocations and duplications in hematological malignancies. This would suggest that oncogene(s) reside in this region. We have cloned the junctional sequence of t(1;14)(q25;q32) in pre-B acute lymphoblastic leukemia cells by an inverse PCR method. A novel sequence was fused to the joining region of the immunoglobulin heavy chain gene. We confirmed this rearrangement by Southern blot analysis, genomic PCR and fluorescence in situ hybridization. We found a coding sequence which is homologous to the mouse Lhx4 cDNA sequence 17 kb from the breakpoint. The human Lhx4 gene encodes 390 amino-acids, including one tandem pair of LIM domains and one homeodomain. The human Lhx4 gene consists of six exons. Lhx4 protein is very homologous to human Lhx3 protein except in the N-terminal region. The transcripts of the Lhx4 gene were not detected in adult multiple tissues analysed by Northern blotting, but were detected in the leukemic cells carrying t(1;14)(q25;q32) by reverse-transcription PCR. The protein expression of Lhx4 in these leukemic cells was confirmed by Western blot analysis. Lhx4 activated the reporter gene carrying the mouse alpha-glycoprotein subunit promoter region, which is regulated by Lhx3. LIM protein and homeodomain protein genes are frequently involved in translocations of hematological malignancies. The Lhx4 gene is deregulated in the leukemic cells and Lhx4 protein may play an important role, possibly as an activator, in leukemogenesis.

Acute Disease↗

PubMed2002

Ancient ubiquitous protein 1 binds to the conserved membrane-proximal sequence of the cytoplasmic tail of the integrin alpha subunits that plays a crucial role in the inside-out signaling of alpha IIbbeta 3.

Modification of the cytoplasmic tails of the integrin alpha(IIb)beta(3) plays an important role in the signal transduction in platelets. We searched for proteins that bind to the alpha(IIb) cytoplasmic tail using the yeast two-hybrid assay with a cDNA library of the megakaryocyte-derived cell line and identified a protein, ancient ubiquitous protein 1 (Aup1), that is ubiquitously expressed in human cells. Observation of UT7/TPO cells expressing a red fluorescent protein-tagged Aup1 indicated its localization in the cytoplasm. Immunoprecipitation of UT7/TPO cells by an antibody for Aup1 revealed that approximately 40% of alpha(IIb) is complexed with Aup1. Binding study with an alpha(IIb) cytoplasmic tail peptide and glutathione S-transferase-Aup1 fusion protein revealed a low affinity (K(d) = 90 microm). Subsequent yeast two-hybrid assay indicated binding of Aup1 to cytoplasmic tails of other integrin alpha subunits. Binding study with the purified Aup1 and various glutathione S-transferase-alpha(IIb) cytoplasmic tail peptides revealed specific binding of Aup1 to the membrane-proximal sequence (KVGFFKR) that is conserved among the integrin alpha subunits and plays a crucial role in the alpha(IIb)beta(3) inside-out signaling. As Aup1 possesses domains related to signal transduction, these results suggest involvement of Aup1 in the integrin signaling.

Amino Acid Sequence↗

PubMed2002

CD3-negative, CD20-positive T-cell prolymphocytic leukemia: case report and review of the literature.

We report a case of CD3-negative, CD20-positive T-cell prolymphocytic leukemia (T-PLL). The leukemic cells were of medium-to-large size, mature-looking, and did not have cytoplasmic granules. The leukemic cells were negative for surface CD3, CD2, and CD7 and strongly positive for CD20. T-cell lineage markers such as CD4, CD5, and cytoplasmic CD3 were also positive. A monoclonal rearrangement of the T-cell receptor (TCR) beta chain gene was detected. CD3-negative T-PLL has been reported often, but CD20-positive T-PLL has not. We reviewed seven cases of CD20-positive immature and mature T-cell leukemias, including the present case. Three were immature T-cell leukemias (acute lymphoblastic leukemia), and four were mature T-cell leukemias (granular lymphocytic leukemia, small lymphocytic lymphoma/chronic lymphocytic leukemia, adult T-cell leukemia, and the present case). Splenomegaly was a common feature. However, our case alone had "bright" CD20 expression on the leukemic cells. This is the first report of CD20(+) T-PLL.

Aged↗

PubMed2002

More than 13 years of hypereosinophila associated with clonal CD3-CD4+ lymphocytosis of TH2/TH0 type.

A 65-year-old Japanese woman was referred to our hospital because of hypereosinophilia lasting for more than 10 years, and skin ulceration, especially on the hands. Closer examination revealed the clonal proliferation of CD3-CD4+T-lymphocytes. The patient had generalized pruritus without severe end-organ involvement and high serum levels of IgE. A diagnosis of monoclonal CD3-CD4+ T-lymphocyte-associated idiopathic hypereosinophilic syndrome (HES) was made based on these findings. This case showed that this newly recognized entity of HES is not restricted to Western countries. The abnormal T-cell clone was not merely TH2 type but was clearly TH2/TH0 type. Although this disease is considered prelymphoma, this patient did not develop lymphoma during more than 13 years of follow-up. Therefore, in some patients, clonal CD3-CD4+ lymphocyte-associated HES may take a more indolent course. In this subgroup, the control of clinical manifestations seems very important. In the present case, treatment with hydroxyurea quite dramatically improved the intractable skin manifestations, although the treatment lessened only the number of peripheral eosinophils and not the number of clonal CD3-CD4+ T-lymphocytes.

Adult↗

PubMed2002

NK cell lymphoma.

Natural killer (NK) cells are lymphocytes with large granular lymphocyte morphology, CD3-CD56+ phenotype, non-MHC-restricted cytotoxicity, and germ-line configuration T-cell receptor genes. Two types of lymphomas originating from NK cells have been described; blastic NK-cell lymphoma, and nasal-type NK-cell lymphoma. Because recent reports indicate that blastic NK-cell lymphoma originates from the precursors of plasmacytoid dendritic cells, I will focus mainly on nasal-type NK-cell lymphoma, and discuss its pathogenesis, diagnostic problems, treatment strategy, and outcome. Nasal-type NK-cell lymphoma develops mostly in the nasal cavity and rarely in other sites, such as the skin and intestinal tract. Epstein-Barr virus (EBV) is found in lymphoma cells of almost all the patients, and is considered to be the etiologic agent. Indeed, EBV easily infects NK cells in the absence of CD21 antigen, or EBV receptor, on the surface of NK cells. Further, various types of oncogenes and suppressor oncogenes are found to be involved in its pathogenesis. Based on the data obtained from paraffin-embedded specimens, it is difficult to determine whether the lymphoma cells are of T-cell or NK-cell lineage, because immunohistochemical staining of cytoplasmic CD3 is positive both in T and NK cells, and CD56 is positive in a part of T cells. The presence of CD5 antigen indicates T-cell lineage. When the disease is limited, radiation therapy is effective, but not satisfactory. A new trial to use simultaneously both radiation and chemotherapy has started in Japan. In advanced stages, a combination chemotherapy including L-asparaginase seems to be promising, and high-dose chemotherapy with autologous or allogeneic stem cell support is under investigation. A recent report described the expression of short-length P-glycoprotein (P-gp), but not full-length P-gp in NK cells, and this mini-P-gp is unable to extrude daunorubicin. These findings may change the treatment strategy. Finally, I will present the results on interim analysis of 166 cases of nasal-type NK-cell lymphoma collected in Japan between 1994 and 1998.

Combined Modality Therapy↗

PubMed2002

Relationship between CD4(+)/CD8(+) T cell ratio and T cell activation in multiple myeloma: reference to IL-16.

We found that the ratio of CD4(+) to CD8(+) T cells (CD4/CD8 ratio) was decreased in patients with multiple myeloma (MM) and that this decrease was significantly related to an increase of human leukocyte antigen (HLA)-DR expression by CD8(+) (but not CD4(+)) T cells (P<0.005). In addition, the serum level of interleukin (IL)-16 was significantly higher in stage III MM patients than in healthy controls (P<0.001). The decrease of CD4(+) T cells in MM may be mediated by activation of CD8(+) T cells derived cytokine IL-16. In addition, these T cell phenotypic changes and the IL-16 level appear to be useful indicators of disease activity.

Biomarkers↗

PubMed2002

Late appearance of t(1;19)(q11;q11) in myelodysplastic syndrome associated with dysplastic eosinophilia and pulmonary alveolar proteinosis.

We report a case of myelodysplastic syndrome (MDS), which developed marked eosinophilia and pulmonary alveolar proteinosis after the appearance of t(1;19)(q11;q11). Chromosomal analysis of the peripheral eosinophils identified the same chromosome abnormality in all metaphases to that of bone marrow blast cells. Review of the literature revealed three reported cases of concurrent MDS and pulmonary alveolar proteinosis. We reviewed four cases of concurrent MDS and pulmonary alveolar proteinosis, including the present case. Interestingly, all but one of these patients also had evidence of eosinophilia and abnormality of chromosome 1p. These findings, together with morphologic abnormalities of eosinophils observed in this case, indicate clonal involvement of eosinophils in the MDS clone, and that the eosinophilia was derived from the neoplastic clone with the translocation. We postulate that this chromosomal rearrangement is involved in the development of eosinophilia and pulmonary alveolar proteinosis in MDS.

Bone Marrow Cells↗

PubMed2002

Mononucleosis syndrome and acute monocytic leukemia.

The association of infectious mononucleosis and an immunocompromised host such as occurs in acute leukemia is reported. The most common cause of infectious mononucleosis is Epstein-Barr virus (EBV) and cytomegalovirus (CMV). Patients with mononucleosis syndrome caused by other agents are rare. We report a case of acute monocytic leukemia (AMoL) who developed varicella zoster virus (VZV) mononucleosis syndrome in the bone marrow recovery phase after myelosuppression due to high-dose cytarabine. Mononuclear leukocytes appearing during the mononucleosis syndrome were very similar to the initial leukemic cells. Varicella zoster virus mononucleosis syndrome was confirmed by delayed herpes zoster rash with dermatomal distribution.

Adult↗

PubMed2002

Epstein-Barr virus-associated T-cell acute lymphoblastic leukaemia.

Epstein-Barr virus (EBV) is frequently detected in haematological malignancies, including Burkitt's lymphomas/leukaemias, Hodgkin's diseases and non-Hodgkin's lymphomas. However, immature T-cell malignancies associated with EBV have not been reported previously. We report a patient with T-cell acute lymphoblastic leukaemia (T-ALL), whose leukaemic cells had EBV, confirmed by Southern blotting and in situ hybridization. The EBV existed in episomal form and was detected in most leukaemic cells, but not in bystander normal B-cells. The leukaemic cells, massively infiltrated into the liver and spleen, were resistant to chemotherapy. EBV might be associated with tumorigenesis of T-ALL, and characteristic clinical features of the patient.

Adult↗

PubMed2002

Low-dose doxorubicin-induced necrosis in Jurkat cells and its acceleration and conversion to apoptosis by antioxidants.

We treated rapidly growing Jurkat cells with 40 nmol/l of doxorubicin for 72 h. After 36 h, the G2-arrested cells became larger and some of them started endoreplication. Nuclear staining with Hoechst 33342 combined with propidium iodide (PI) exclusion revealed that about 90% of the cells were necrotic at 72 h, although apoptotic cells accounted for only 8%. Incubation with 40 nmol/l of aclarubicin or cytosine beta-d-arabinofuranoside for 60 h induced necrosis both in Jurkat and ml-1 cells. Pre-necrotic Jurkat cells incubated with 40 nmol/l of doxorubicin had much higher intracellular reactive oxygen species (ROS) levels than pre-apoptotic ones. Addition of Tempol or Desferal accelerated doxorubicin-induced necrosis and partially converted it into apoptosis. Both antioxidants reduced surviving colony numbers of prenecrotic Jurkat cells. n-acetyl-l-cysteine had little effect on the apoptotic conversion but profoundly accelerated necrosis. Because an apoptosis-resistant Jurkat subclone was also refractory to doxorubicin-induced necrosis, apoptosis and necrosis might share some common pathways. Low-dose doxorubicin increased micronuclei-positive cell percentages and also suppressed high-dose doxorubicin-induced apoptosis in Jurkat and ml-1 cells. Some of the prenecrotic cells, therefore, might survive and obtain genomic instability. Antioxidants may be useful to suppress, at least to some extent, this vicious consequence.

Antineoplastic Agents↗

PubMed2002

Molecular analysis of oncogenes, ras family genes (N-ras, K-ras, H-ras), myc family genes (c-myc, N-myc) and mdm2 in natural killer cell neoplasms.

Natural killer (NK) cell neoplasms are rare diseases. Frequent abnormalities of the tumor suppressor genes Rb, p53, p15INK4B, p16INK4A and p14ARF have been reported. However, no oncogenes associated with tumorigenesis of NK cell neoplasms have been reported so far. We analyzed the status of oncogenes including N-ras, K-ras, H-ras, c-myc, N-myc and mdm2 by Southern blot, PCR-SSCP, western blot analysis and immunohistochemical staining. We analyzed four cell lines derived from NK cell neoplasms and 31 clinical samples with five subclasses of NK cell neoplasms. We found no point mutations of the ras family genes. We detected no mutations in the c-myc and N-myc genes. No overexpression of c-Myc protein was detected by western blot analysis. Although we found neither amplification nor rearrangement of the mdm2 gene, we found high expression of MDM2 protein in some cases by western blot analysis. Immunohistochemical staining confirmed the overexpression of MDM2 protein. We found 14 cases with overexpression of MDM2 protein out of 15 cases (93%) with four subclasses of NK cell neoplasms except chronic NK lymphocytosis. Our previous and these results suggested that the expression level of MDM2 protein is independent of the status of the p14ARF, p53, Rb genes. MDM2 protein might independently contribute to carcinogenesis of NK cell neoplasms. Although the number of the cases we analyzed was not large, alterations of ras and myc family genes may rarely contribute to tumorigenesis in NK cell neoplasms. In contrast, overexpression of MDM2 might be associated with tumorigenesis of NK cell neoplasms, especially aggressive subclasses.

Blotting, Southern↗