Measurement of the D*+/- cross section in two-photon processes.
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Journal Article↗
Biomedical subjects
T Tauchi
Publications and source records attributed to T Tauchi.
SH2-containing phosphotyrosine phosphatase Syp is a target of p210bcr-abl tyrosine kinase.
The phosphorylation of proteins at tyrosine residues is critical in cellular signal transduction and neoplastic transformation. These mechanisms are regulated by the activities of both protein-tyrosine kinases and protein-tyrosine phosphatases. Recent studies have identified a novel protein-tyrosine phosphatase, termed Syp, that is widely expressed in various tissues. Syp encodes a cytoplasmic phosphatase that contains two Src homology 2 (SH2) domains. Since SH2 domains have been shown to target the association of signal-transducing molecules to activated tyrosine kinases, experiments were performed to determine whether Syp might form specific complexes with p210bcr-abl, a fusion protein believed to be involved in the pathogenesis of chronic myelogenous leukemia and, thus, possibly alter or mediate p210bcr-abl tyrosine kinase activity. We found that Syp was highly and constitutively tyrosine phosphorylated in three different murine cell lines transfected with a p210bcr-abl expression vector. Furthermore, p210bcr-abl, Syp, and Grb2 formed stable complexes in BCR-ABL-expressing cells. Complex formation between p210bcr-abl and Syp was mediated in vitro by the NH2-terminal SH2 domain of Syp. Last, p210bcr-abl tyrosine kinase was effectively dephosphorylated by Syp in vitro. These results suggest an interaction between Syp and BCR-ABL protein, which might play a role in cellular transformation of BCR-ABL.
Animals↗
Coupling between p210bcr-abl and Shc and Grb2 adaptor proteins in hematopoietic cells permits growth factor receptor-independent link to ras activation pathway.
Enforced expression of p210bcr-abl transforms interleukin 3 (IL-3)-dependent hematopoietic cell lines to growth factor-independent proliferation. It has been demonstrated that nonreceptor tyrosine kinase oncogenes may couple to the p21ras pathway to exert their transforming effect. In particular, p210bcr-abl was recently found to effect p21ras activation in hematopoietic cells. In this context, experiments were performed to evaluate a protein signaling pathway by which p210bcr-abl might regulate p21ras. It was asked whether Shc p46/p52, a protein containing a src-homology region 2 (SH2) domain, and known to function upstream from p21ras, might form specific complexes with p210bcr-abl and thus, possibly alter p21ras activity by coupling to the guanine nucleotide exchange factor (Sos/CDC25) through the Grb2 protein-Sos complex. This latter complex has been previously demonstrated to occur ubiquitously. We found that p210bcr-abl formed a specific complex with Shc and with Grb2 in three different murine cell lines transfected with a p210bcr-abl expression vector. There appeared to be a higher order complex containing Shc, Grb2, and bcr-abl proteins. In contrast to p210bcr-abl transformed cells, in which there was constitutive tight association between Grb2 and Shc, binding between Grb2 and Shc was Steel factor (SLF)-dependent in a SLF-responsive, nontransformed parental cell line. The SLF-dependent association between Grb2 and Shc in nontransformed cells involved formation of a complex of Grb2 with c-kit receptor after SLF treatment. Thus, p210bcr-abl appears to function in a hematopoietic p21ras activation pathway to allow growth factor-independent coupling between Grb2, which exists in a complex with the guanine nucleotide exchange factor (Sos), and p21ras. Shc may not be required for Grb2-c-kit interaction, because it fails to bind strongly to c-kit.
Adaptor Proteins, Signal Transducing↗
Hypomethylated status, but not RAG-1, is required for T-cell receptor-beta-chain gene rearrangement in acute leukemia cells.
We studied the relation between the level of recombinase activating gene (RAG-1) and the methylation status of T-cell receptor (TCR)-beta-chain gene in TCR-beta rearrangement in acute leukemias, including 21 patients with B-precursor acute lymphoblastic leukemia (ALL) and 23 with acute myeloid leukemia (AML). The rearrangement of the TCR beta-chain gene in acute leukemia always occurs at the allele that contains hypomethylated cytosine-cytosine- guanine-guanine (CCGG) sequences within either the TCR-J beta 1 or TCR-J beta 2 regions. Moreover, all B-precursor ALL patients with TCR-beta rearrangement had hypomethylated TCR-beta with or without the presence of RAG-1 activity detectable by reverse transcript-polymerase chain reaction, whereas none of the AML patients with TCR-beta rearrangement and hypomethylated TCR-beta had detectable RAG-1 activity. Some ALL patients had hypomethylated TCR-beta and RAG-1 activity without TCR-beta rearrangement, and most of them showed t(4;11)(q21;q23) or t(9;22)(q34;q11). These results indicate a correlation between the hypomethylation status of the TCR-beta and its rearrangements, but some unknown blockage factor for this association exists in B-precursor ALL patients with specific chromosomal translocations.
Acute Disease↗
Cytogenetic and immunogenotypic alterations of blast crisis cells in chronic myelogenous leukemia independently linked to immunophenotypic expression.
Chronic myelogenous leukemia (CML) is a disease of the hematopoietic stem cells, which can differentiate into either B-lymphoid or myeloid cells, because most of them develop either lymphoid or myeloid blast crisis. Immunophenotypic, genotypic, and cytogenetic analyses of 22 patients (24 episodes) with Philadelphia (Ph) positive CML in blast crisis were performed to determine the genetic alterations of the blast crisis cells. In B-lymphoid blast crisis, all the five patients had immunoglobulin heavy-chain (IgH) rearrangements and most of them showed normal karyotypes. Among the five patients, T-cell receptor (TCR) genes were rearranged at the following occurrence rates: 20% in TCR-beta, 60% in TCR-gamma, and 40% in TCR-delta chain genes. A high incidence of additional chromosome changes was noted in patients with B-lymphoid/myeloid-mixed blast crisis, but about 80% of them had rearranged IgH and about 40% had TCR rearrangements. In contrast, most of the patients with non-lymphoid blast crisis showed further chromosomal abnormalities, including +8, +19, i(17q), and double Ph, and most of them had germline configurations of IgH and TCR-gamma chain genes. Notably, only one patient (dual lymphoid and myelomegakaryoblast crisis) in this group exhibited IgH rearrangement, and TCR-beta and TCR-delta rearrangements were also rarely noted. Rearrangement of the IgH gene in CML blast crisis might be linked to expression of lymphoid markers, especially CD19.
Antibodies, Monoclonal↗
Role of p21 RAS in p210 bcr-abl transformation of murine myeloid cells.
The p21 RAS product has been implicated as part of the downstream signaling of certain nonreceptor tyrosine kinase oncogenes and several growth factor receptor-ligand interactions. We have reported that the chronic myelogenous leukemia oncogene p210 bcr-abl transforms a growth-factor-dependent myeloid cell line NFS/N1.H7 to interleukin-3 (IL-3) independence. In these p210 bcr-abl-transformed cells (H7 bcr-abl.A54) and in two other murine myeloid cell lines transformed to IL-3 independence by p210 bcr-abl, endogenous p21 RAS is activated as determined by an elevated ratio of associated guanosine triphosphate (GTP)/guanosine diphosphate (GDP), assayed by thin-layer chromatography of the nucleotides eluted from p21 RAS after immunoprecipitation with the Y13-259 antibody. Treatment of p210 bcr-abl-transformed cells with a specific tyrosine kinase inhibitor herbimycin A resulted in diminished tyrosine phosphorylation of p210 bcr-abl and associated proteins, without major reduction in expression of the p210 bcr-abl protein itself. Inhibition of p210 bcr-abl-dependent tyrosine phosphorylation resulted in a reduction of active p21RAS-GTP complexes in the transformed cells, in diminished expression of the nuclear early response genes c-jun and c-fos, and in lower cellular proliferation rate. To further implicate p21 RAS in these functional events downstream of p210 bcr-abl tyrosine phosphorylation, we targeted G-protein function directly by limiting the availability of GTP with the inosine monophosphate dehydrogenase inhibitor, tiazofurin (TR). In p210 bcr-abl-transformed cells treated for 4 hours with TR, in which the levels of GTP were reduced by 50%, but GDP, guanosine monophosphate, and adenosine triphosphate (ATP) were unaffected, p210 bcr-abl tyrosine phosphorylation was at control levels. However, expression of c-fos and c-jun nuclear proto-oncogenes were strongly inhibited and p21 RAS activity was downregulated. These findings show that p210 bcr-abl transduces proliferative signals, in part, through downstream activation of p21 RAS. Furthermore, p21 RAS activity is linked to pathways that regulate c-jun and c-fos expression.
Animals↗
The methylation status of the major breakpoint cluster region in human leukemia cells, including Philadelphia chromosome-positive cells, is linked to the lineage of hematopoietic cells.
The Philadelphia (Ph) translocation [t(9;22)(q34;q11)] is the most common genetic abnormality in human leukemia; a transposition of the ABL gene to the major-breakpoint cluster region (M-BCR) is associated with the pathogenesis in Ph+ chronic myelogenous leukemia (Ph+ CML) and in some cases of Ph+ acute leukemia (Ph+ AL). Our current understanding of the methylation of human genomes allows us to consider the association between the epigenetic phenomenon and the control of differentiation and proliferation in mammalian cells. In order to determine whether the methylation status of the M-BCR is associated with breakpoint-localization in this region and with the lineage of hematopoietic cells, we have examined 28 patients with Ph+ leukemias, including nine with Ph+ AL, six patients with acute myeloblastic leukemia without Ph (Ph- AML), and five patients with Ph- acute lymphoblastic leukemia (Ph- ALL); using the restriction endonuclease isochizomers, MspI and HpaII. In CML patients in the chronic phase, the hypomethylated status within the normal M-BCR allele is heterogeneous. In contrast, patients with Ph+ CML in the lymphoid blast crisis phase exhibited a 2.5/2.7 kb band with a complete disappearance of the germline M-BCR fragment (type L). This pattern is consistently noted in Ph- ALL cells, and the pattern is quite different from that found in myeloid blast crisis or Ph- AML (type M). In patients with M-BCR-nonrearranged Ph+ ALL, it is suggested that the M-BCR methylation patterns are cell-lineage specific but some Ph+ ALL cells had a hypomethylation pattern that was identical to that observed in Ph- AML, suggesting a distinction of genetic diversity of leukemia cells with the Ph chromosome, especially Ph+ AL.
5-Methylcytosine↗
T-cell receptor beta chain gene rearrangement in acute myeloid leukemia always occurs at the allele that contains the undermethylated J beta 1 region.
The epigenetic phenomenon could play a role in the interaction between chromatin and DNA-binding enzymes, allowing us to consider an association between the phenomenon and gene rearrangement. The correlation between methylation status and rearrangement of the T-cell receptor (TCR) beta chain gene in leukemia cells obtained from patients with acute myeloid leukemia (AML) was examined. All of the AML patients with a TCR-beta rearrangement had hypomethylated CCGG sequences within the J beta 1 region on the rearranged allele, while the germline allele had completely methylated CCmeGG sequence in this region, indicating a strong association between hypomethylation status and rearrangement of the TCR beta chain gene. In the DNA from AML patients with or without a TCR-beta rearrangement, the C beta 2 region contained completely methylated CCmeGG sequences, even though they express T-cell-associated antigens, including CD7; this pattern is quite different from that observed in T-cell neoplasias. Moreover, some AML patients showed a TCR-beta rearrangement without the presence of immunoglobulin heavy-chain gene rearrangement, suggesting that TCR beta chain gene involvement in AML is required for unknown factors other than common recombinase activity.
Adolescent↗
Cytogenetic and clinical findings of myelodysplastic syndromes with a poor prognosis. An experience with 97 cases.
BACKGROUND: Clinical and cytogenetic analyses were performed in 97 patients with myelodysplastic syndromes (MDS) to evaluate risk factors for poor prognosis. METHODS/RESULTS: Among them, 22 patients survived for less than 1 year: 10 of these had complex chromosomal abnormalities (complex aberrations), but only 5 of the remaining 75 patients who survived longer than 12 months did. Leukemia did not develop in approximately half of the patients who died within 1 year. The occurrence rate of leukemic transformation appears to depend on MDS subtypes rather than cytogenetic changes. In contrast, the percentage of patients who survived for less than 1 year is related to chromosomal changes, especially to complex aberrations. Of particular interest in this study is that 7 of 11 patients with MDS who had myelofibrosis survived for less than 1 year, and 5 of 7 patients with secondary MDS were included in this group showing a poor prognosis. By hematologic analysis, significant differences were found in the hemoglobin values and platelet counts of patients who survived for less than 1 year. CONCLUSIONS: From this analysis, three major risk factors for a poor prognosis were identified: complex aberrations, a history of chemotherapy or radiation therapy (secondary MDS), and development of myelofibrosis. The survival probability in the patients with MDS having at least one of these three factors was significantly low when compared with that in patients without these factors, indicating that cytogenetic analysis in combination with observance of certain clinical manifestations is important in therapeutic management of patients with MDS.
Anemia, Refractory, with Excess of Blasts↗
Restoration of cytogenetically normal marrow cells after remission of lymphoblastic crisis in a case of Ph positive CML treated with alpha-interferon.
A patient with Philadelphia (Ph) chromosome-positive chronic myelogenous leukemia (CML) who was treated with alpha-interferon (alpha-IFN) is reported. After the treatment, the number of Ph+ bone marrow (BM) cells decreased gradually and the intensity of the rearranged major breakpoint cluster region (M-BCR) gene became faint; however, a lymphoblastic crisis developed about 1 year later. At the time of the blast crisis, the rearranged M-BCR band was detected, indicating that the blast crisis clone was derived from CML cells. The patient was treated with a combination of vincristine, prednisolone, daunorubicin, and L-asparaginase, and a hematologic remission was obtained. During the remission status, no rearranged M-BCR fragment was detected by conventional Southern analysis. Thus, the hematologic and genetic alteration in this case appeared to be identical to Ph+ acute leukemia with M-BCR rearrangement. The current case therefore indicates that alpha-IFN can reduce the proportion of Ph+ cells, but is unable to prevent blast crisis. Furthermore, the quantitative reduction of the cell population with a Ph chromosome may have some effects in modifying the genetic manifestations and clinical features of Ph+ CML, e.g., the delay in the appearance of the blast crisis.
Antigens, CD↗
Leukemic phase of intermediate non-Hodgkin's lymphoma with cells showing different matured stages in invaded various organs.
A 56-year-old male was admitted to our hospital with lymphocytosis (16.4 x 10(9)/l; 79% lymphocytes including 50% small lymphocytes), generalized lymphadenopathy, massive splenomegaly, and heavily infiltrated bone marrow. Immunophenotype analysis of the neoplastic cells in the bone marrow revealed that they were B cells (CD20 + CD19 + Ia1 + sIgM+) positive for CD10. By contrast, the cells in the lymph node were CD20 + CD19 + Ia1 + sIgM+ but negative for CD10. The patient was tentatively diagnosed as having lymphosarcoma cell lymphoma, however, the final diagnosis was leukemic phase of intermediate lymphocytic lymphoma. We concluded that CD10+ neoplastic cells in the bone marrow and peripheral blood had differentiated to CD10- cells.
Antigens, Differentiation↗
Immunogenotypes and clonal culture analysis in B-precursor acute lymphoblastic leukemia.
Immunogenotypic changes in 32 patients with B-precursor acute lymphoblastic leukemia (ALL), including three patients with t(4;11) and 13 with t(9;22), were determined using immunoglobulin heavy (IgH) chain gene probe and T-cell receptor beta, gamma and delta chain gene probes. Clonogenic assay was performed in 12 of the 32 patients. In this study, four patients had a germline configuration of the IgH chain gene, showing a dissociation between phenotypic and genotypic expression; three patients had Philadelphia-positive (Ph+) ALL. The immunogenotypic manifestation in Ph+ ALL does not depend on whether the leukemia cells had rearrangement within the major breakpoint cluster region (major-BCR) DNA sequence or the leukemia cells had myeloid-associated antigens. Colony assay using various recombinant cytokines demonstrated that the leukemia cells from four of 12 patients formed colonies in response to myelopoietic stimulants; three of the four patients were major-BCR-rearranged Ph+ ALL. Notably, cells from one patient with Ph+ ALL formed colonies on the addition of granulocytic colony-stimulating factor. This indicates not only the biological heterogeneity of ALL cells but also that some of the characteristics of the cells are related to specific chromosome changes.
Adult↗
[Molecular biology and FAB classification].
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Adult↗
Translocation (2;16)(p11;q22) and trisomy 22 in acute myelogenous leukemia (FAB M2) with bone marrow eosinophilia.
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Adult↗
Clinical and cytogenetic characteristics of myelodysplastic syndromes developing myelofibrosis.
Myelofibrosis occurs in various hematologic neoplasias, including myelodysplastic syndrome (MDS), with a relatively low incidence. To gain insight into the clinical and cytogenetic implications of MDS patients in whom myelofibrosis develops, statistical analysis was done on 82 primary MDS patients with successful cytogenetic results. Seven patients had myelofibrosis during the course of the disease (8.5%, Group I), 34 had abnormal karyotypes without myelofibrosis (41.5%, Group II), and the other 41 had abnormal karyotypes without myelofibrosis (50%, Group III). All of the MDS patients except one with myelofibrosis had cytogenetic abnormalities, and four of them had multiple chromosome abnormalities. In univariant analysis, MDS patients with myelofibrosis showed no significant differences in age, sex, or peripheral blood data. In contrast, patients with chromosome abnormalities evolved into myelofibrosis with a high incidence compared with those with normal karyotypes (14.6% versus 2.4%, P = 0.054). The occurrence of myelofibrosis was higher during the first 6 months after the diagnosis of MDS than in the next 6 months (6.1% versus 0%, P = 0.045). Most of the MDS patients survived for less than 10 months after myelofibrosis was evident. Furthermore, survival was significantly shorter in Group I compared with Groups II (P less than 0.05) and III (P less than 0.01). Among the MDS patients in whom myelofibrosis developed, some were associated with acute megakaryoblastic leukemia, indicating a heterogeneity of clinical features in MDS with myelofibrosis.
Adult↗
Methylation status of T-cell receptor beta-chain gene in B precursor acute lymphoblastic leukemia: correlation with hypomethylation and gene rearrangement.
Epigenetic changes may play a role in genetic alterations in cancer cells, but little is known about this phenomenon. In this study we examined the correlation between rearrangement and methylation status of the T-cell receptor (TCR) beta-chain gene in 23 patients with B precursor acute lymphoblastic leukemia (ALL). In B precursor ALL, all patients had a CCmeGG sequence in the C beta 2 region, a pattern similar to that observed in normal mature B-cells. Approximately 55% of patients with B precursor ALL exhibiting a hypomethylated CCGG sequence at the J beta 1 region showed rearrangement of this region. Furthermore, the same allele of rearranged J beta 1 always contained an unmethylated sequence in the region, although another allele without rearrangement contained methylated J beta 1. By contrast, none of the patients had a rearrangement in the J beta 1 region without hypomethylation. Therefore, rearrangement of the J beta 1 region may link to the hypomethylation status of this region. A close association between hypomethylation of the J beta 1 region may promote accessibility to a putative common recombinase to produce TCR J beta 1 rearrangement. In contrast, about 45% of patients with a hypomethylated J beta 1 did not show rearrangement in this region, thus allowing categorization of B precursor ALL patients into subtypes, according to the combination of TCR beta-chain gene rearrangement and hypomethylation status, especially in the J beta 1 region.
Burkitt Lymphoma↗
[A case of myelodysplastic syndrome with abnormal chromosome t (3;4), proliferation of megakaryocytes and myelofibrosis, transition to overt leukemia].
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Aged↗
Acute lymphoblastic leukemia with azurophilic granules that contain ultrastructural myeloperoxidase activity.
We present a case of acute lymphoblastic leukemia (ALL) in which the leukemic cells had cytoplasmic azurophilic granules. Surface marker studies revealed that the leukemic cells expressed CD10 (CALLA), CD19, CD20, and HLA-DR antigens. Cytochemical studies by light microscopy revealed that the blasts were negative for myeloperoxidase, PAS staining, and double esterase staining, supporting the diagnosis of ALL. However, an ultrastructural study demonstrated that some of the cytoplasmic granules were myeloperoxidase (MPO) positive. Our findings suggested that leukemic transformation in this case may have taken place at a stage ontogenetically close to the pluripotent stem cell. Furthermore, the present case indicates the existence of a new form of ALL is characterized by MPO-positive granules detectable by ultracytochemistry and lymphoid-associated surface markers.
Antigens, CD19↗