Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We describe the clinical and laboratory findings of 78 adult patients with T-prolymphocytic leukemia (T-PLL) studied over the last 12 years. The main disease features were splenomegaly (73%), lymphadenopathy (53%), hepatomegaly (40%), skin lesions (27%), and a high leukocyte count (greater than 100 x 10(9)/L in 75%) with nucleolated prolymphocytes. A variant form with small, less typical cells was recognized in 19%. Membrane markers defined a postthymic phenotype TdT-, CD2+, CD3+, CD5+, CD7+; in 65%, the cells were CD4+ CD8-, in 21%, they coexpressed CD4 and CD8, and, in 13%, they were CD4- CD8+. Serology for human T-cell leukemia/lymphoma virus Type-I (HTLV-I) was negative in the 27 cases investigated. Cytogenetic analysis in 30 cases showed a consistent abnormality of chromosome 14, usually inv (14), with breakpoints at q11 and q32 in 76% of cases. Trisomy 8, including iso8q, was shown in 53%; t (11;14)(q13;q32) was documented in one case; and one had a normal karyotype. The clinical course was progressive with a median survival of 7.5 months. Thirty-one patients were treated with 2' deoxycoformycin and 15 responded (3 complete remissions and 12 partial remissions); the response rate (48%) increased to 58% in patients with a CD4+ CD8- phenotype. The median survival of responders was 16 months and of nonresponders 10 months; other treatments were less effective. T-PLL is a distinct clinico-pathologic entity with aggressive course and characteristic chromosome abnormalities. A subgroup of patients may benefit from deoxycoformycin.
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PMID:Clinical and laboratory features of 78 cases of T-prolymphocytic leukemia. 174 86

In this prospective study we investigated the frequency of CD10+, TdT+ and CD10+TdT+ mononuclear cells in the bone marrow (BM) and peripheral blood (PB) before and after autologous bone marrow transplantation (ABMT). 49 patients treated for acute lymphoblastic or myeloblastic leukaemia, malignant lymphoma or multiple myeloma were included. A significant increase in CD10+ cells occurred in BM in both children and adults after ABMT. In children, we also found a significant increase in CD10+ cells in PB. In individual patients remaining in remission, up to 34% CD10+ cells having a normal Ig kappa/lambda light chain ratio were recorded after ABMT. In children, the percentage of TdT+ and CD10+ TdT+ cells increased significantly in BM. In most cases the CD10/TdT-ratio was greater than 1.0, but during early regeneration after ABMT this ratio was less than 1.0 in several patients remaining in complete remission. In patients remaining in remission, CD10+TdT+ cells were detected in the blood in only 2 out of 140 samples tested, and the proportion of these cells never exceeded 0.03%. We conclude that quantitation of CD10+TdT+ cells in peripheral blood is helpful in the evaluation of complete remission in patients treated for pre-B-ALL.
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PMID:Regeneration of CALLA (CD10+), TdT+ and double-positive cells in the bone marrow and blood after autologous bone marrow transplantation. 182 71

2'-Deoxy-6-thioguanosine 5'-triphosphate (S6dGTP), a metabolite of the antileukemia agent 6-thioguanine, was evaluated as a substrate for purified human DNA polymerases. Using bacteriophage M13 single-strand DNA as a template, S6dGTP substituted efficiently for dGTP and stimulated DNA synthesis in reactions without dGTP, with DNA polymerases alpha, delta, and gamma from the human leukemia cell line K562. The apparent Km values for dGTP and S6dGTP were very similar, i.e., 1.2 microM each for polymerase alpha, 2.8 and 3.6 microM, respectively, for polymerase delta, and 0.8 microM each for polymerase gamma; however, the relative Vmax values for the modified nucleotide were 25-50% lower than those of the corresponding natural substrate. Using a highly sensitive electrophoretic assay of chain elongation across M13mp9 (+)-strand DNA by the aforementioned human DNA polymerases, S6dGTP was shown to be incorporated at the 3' end of the nascent growing DNA chain, and the patterns of chain extension with S6dGTP as substrate were identical to those obtained in the presence of dGTP. There were no major differences using S6dGTP in place of dGTP with these DNA polymerases; however, at higher concentrations (1-10 microM) the analog stimulated primer elongation in reactions without dATP, indicating some misincorporation at sites of S6G.T base pairs during DNA synthesis. Using p(dA)12-18 as the initiator for calf thymus terminal deoxynucleotidyltransferase, S6dGTP inhibited the incorporation of all four natural deoxyribonucleoside 5'-triphosphates into the primer, in a competitive manner. The apparent Ki values for the analog were 6-20 times lower than the Km values for the four endogenous substrates. As a substrate, S6dGTP was added to the 3'-hydroxyl termini of primer, although tailing efficiency with the analog was lower than that in the presence of the natural substrate. These findings indicate that S6dGTP is a relatively good substrate for several mammalian DNA polymerases, including terminal deoxynucleotidyltransferase.
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PMID:2'-Deoxy-6-thioguanosine 5'-triphosphate as a substrate for purified human DNA polymerases and calf thymus terminal deoxynucleotidyltransferase in vitro. 192 85

Nuclear matrix extracted from KM-3, a human pre-B leukemia cell line, appears to have a site of linkage for terminal deoxynucleotidyl transferase (TdT). The immunocytochemical analysis of the distribution of TdT using a rabbit polyclonal antibody which recognizes human terminal transferase, shows that the nuclear framework of these cells contains sites of immunoreactivity that appear uniformly distributed on the matrix fibres, while the nucleolar region is unreactive. This evidence points out the possibility that TdT could reside in the proteinaceous scaffold of the nucleus defined as nuclear matrix, thus strengthening the evidence for the metabolic and regulatory roles ascribed to this nuclear framework.
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PMID:Association between nuclear matrix and terminal transferase: an electron microscope immunocytochemical analysis. 193 81

A 37-year-old male from Kagoshima Prefecture was admitted with adult T-cell leukemia (ATL). Monoclonal integration of HTLV-1 proviral DNA was found, but the integration site was different from that of terminal deoxynucleotidyltransferase (TdT)-positive MT-1 cells (an ATL cell line). The ATL cells expressed enzymatically active TdT and exhibited 2100 b TdT mRNA, which corresponds to the thymus type of TdT mRNA. The same size of TdT mRNA was also detected in MT-1. Southern blot analyses revealed no differences in the gene structure of the promoter region of TdT genes between this ATL case and TdT-positive lymphoblastic leukemia cells. There is little possibility that cis-acting viral elements promote TdT gene expression by proviral integration. The activation of TdT gene in ATL may be mediated by other trans-acting factors.
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PMID:Expression of terminal deoxynucleotidyltransferase gene in a case of adult T-cell leukemia. 195 50

Monosomy 7 as the sole cytogenetic abnormality was detected in five of 310 consecutive adult patients with acute leukaemia who were characterized by morphological, immunophenotypic and cytogenetic analyses. Morphologically, blast cells were myelomonocytic (FAB M4) in three and lymphoid (FAB L2) in two patients. By immunophenotyping, two M4 patients expressed terminal transferase (TdT) in 15-90% of myelomonoblasts (patients 3 and 1, respectively), and in the third M4 patient (no. 2), a 10% TdT+ component was present distinct from the bulk of myelomonoblasts. In one L2 patient (no. 4), the blast cells had an undifferentiated phenotype only expressing TdT and HLA-DR but lacking specific lymphoid and myeloid antigens, and patient 5 was typed as CD10+ ALL. Two patients had developed leukaemia following radiotherapy and/or chemotherapy for multiple myeloma or breast cancer. In two patients, induction chemotherapy induced a lineage switch in the immunophenotype without change in karyotype. These observations support the concept that monosomy 7 leukaemia results from the transformation of a multipotential stem cell.
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PMID:Monosomy 7 in multilineage and acute lymphoblastic leukaemia. 195 71

Mice transgenic for gamma 2b Ig heavy chain were examined for alterations in B-cell differentiation and endogenous Ig gene rearrangement and expression. Fresh bone marrow from these mice was markedly reduced in BP-1+ cells and there were small reductions in B220+ and sIg+ cells. A-MuLV (Abelson murine leukemia virus) transformants from these bone marrow cells showed little alteration in Ig gene rearrangement and expression when compared to controls, however. Isolation of the B-lymphoid compartment from these mice in vitro using LBMC (lymphoid bone marrow cultures) enabled more detailed characterization of the effects of the transgene. LBMC derived from gamma 2b transgenic mice had similar growth kinetics, but a 4-5-week delay in the expression of endogenous mu Ig in comparison to control cultures. Nucleic acids derived from these early cultures prior to endogenous mu Ig expression showed reduced Ig JH rearrangements, some sterile mu transcription, low levels of BP-1 expression, and virtually undetectable TdT (terminal deoxynucleotidyl transferase) expression. Thus, this gamma 2b transgene appears able to affect early B-lymphocyte development.
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PMID:Delay of early B-lymphocyte development by gamma 2b immunoglobulin transgene: effect on differentiation-specific molecules. 196 16

Certain combinations of differentiation antigens are expressed on leukemia blasts and are absent or extremely rare among normal progenitors in the fetal liver and fetal and regenerating bone marrow. These combinations include cCD3/TdT, a thymic feature retained on thymic-acute lymphoblastic leukemia (T-ALL) blasts outside the thymus, and the coexpression of TdT and myeloid markers (CD13, CD33) on a proportion of ALL and acute myeloid leukemia (AML). Thus, double marker immunofluorescence assays are operationally leukemia-specific and can be applied in 35% of acute leukemias for detecting minimal disease at a less than 10(-4) level; only rare cases, 2 of 35 in our study, switch these relevant features during relapse. The sensitivity and specificity of these assays was tested as follows. First, bone marrow samples taken from patients who had originally presented with blasts expressing the leukemia-associated combinations but were in full morphologic remission were studied, and varying numbers (less than 0.01% to 10% of the mononuclear fraction) of cells with aberrant features were identified in 11.6% of the cases. Second, the outcome of 19 patients with minimal disease identified immunologically while in complete morphologic remission was investigated: all 19 patients have developed systemic relapse within 4 to 25 (median 14.5) weeks. In contrast, 17 of 25 patients also morphologically in complete remission and without residual disease identifiable immunologically after repeated testing are still in morphologic and immunologic remission (follow-up 17 to 114 weeks, median 28 weeks). Only eight patients in this group have relapsed so far: in two patients the relapse was localized in the cerebrospinal fluid, while in six patients a systemic relapse was observed 6 to 51 (median 21.5) weeks after the last negative immunologic bone marrow examination. In conclusion, no false-positive results were detected with these sensitive assays, and the introduction of appropriately planned prospective studies, including the immunologic detection of residual leukemia, is justified on the basis of these observations.
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PMID:The immunologic detection of minimal residual disease in acute leukemia. 197 61

In this study we applied double color immunofluorescence analysis and polymerase chain reaction (PCR) amplification of rearranged TCR delta genes for detecting residual leukemia in the posttreatment bone marrow (BM) samples taken from four patients in morphological remission. In three of these patients (nos. 1-3; T-ALL) a combination of CD3 and anti-TdT antibodies (Abs) was used to identify residual blasts while in patient 4 (B lineage ALL) the combination CD13/TdT served to detect residual disease. Two rounds of PCR primed by nested amplimers were carried out to prepare clonospecific probes from presentation DNA and to investigate the follow-up samples. In patients 1 and 2 no cCD3+/TdT+ cells were seen posttreatment, but PCR amplification of the TCR V delta 1-D-J delta 1 region revealed residual disease in both patients. Patient 1 underwent allogeneic BM transplant (BMT) 8 months after diagnosis and is well 3 months post-BMT while patient 2 relapsed 12 months after presentation. In patient 3 the remission samples investigated 2 and 3 months after diagnosis did not contain cCD3+/TdT+ cells, but in the sample collected at 4 months a few such cells (0.0001-0.001%) could be detected. In the same sample, PCR amplification of the TCR V delta 2-D-J delta 1 region indicated the presence of 10(-4)-10(-3) residual leukemic cells. These findings predicted full morphological relapse which occurred 2 months later. In patient 4 CD13/TdT double positive cells were clearly seen 2 and 3 months after presentation. PCR amplification of the V delta 2-D delta 3 recombination also revealed residual blasts when applied to one of such "remission" samples. After further remission induction treatment, no immunologic evidence of residual disease was detected. This patient received an allogeneic BMT 8 months after diagnosis and is disease free 4 months after BMT. Our data indicate that both double color immunofluorescence and PCR analysis offer powerful tools to study residual leukemia and highlight the advantages as well as the potential limitations of each technique.
Leukemia 1990 Sep
PMID:The detection of residual acute lymphoblastic leukemia cells with immunologic methods and polymerase chain reaction: a comparative study. 197 35

Immunotherapy with recombinant human Interleukin-2 (rhIL-2) was given to nine patients in first complete remission from acute myeloid leukaemia (AML). Five patients relapsed. The median time to relapse after commencing rhIL-2 was 26 weeks (range 2-44). Four patients were studied at relapse. The morphological and cytochemical features at relapse and presentation were similar. Cytogenetic analysis at relapse in patients 1 and 3 showed a normal karyotype. At relapse, patient 4 had the abnormality 46,XY, t(2;3). Patient 2 had the chromosomal abnormality t(8;21) at presentation and relapse. Patients 3 and 4 with M5 AML relapsed rapidly at 2 and 9 weeks after starting rhIL-2 treatment. Relapse leukaemia cells had features normally associated with lymphoid development. Patient 3 was TdT positive, with rearranged immunoglobulin genes, and a proportion of cells expressing the CD7 antigen; patient 4 also expressed the CD7 antigen. Relapse leukaemic cells from three of four patients expressed the alpha chain of the IL-2 receptor as assessed by flow cytometry. After overnight incubation and removal of T-lymphocytes the proportion of cells from these patients expressing the alpha chain increased from 15% to 61% (P less than 0.01). Using tritiated thymidine uptake to assess cell proliferation, two of three patients who expressed the IL-2 receptor alpha chain proliferated in response to 1000 u/ml of rhIL-2 in vitro, with a stimulation index greater than 1.95 (P less than 0.05). Following rhIL-2 immunotherapy for AML, relapse cells may express an inducible form of the alpha chain of the IL-2 receptor, which can mediate a proliferative response. It is possible that rhIL-2 when administered to AML patients in remission, may induce relapse. This may be a particular risk in patients with the M5 subtype.
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PMID:Acute myeloid leukaemia relapsing following interleukin-2 treatment expresses the alpha chain of the interleukin-2 receptor. 195 99


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