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Biomedical subjects

M F Greaves

Publications and source records attributed to M F Greaves.

At least 109 records · Page 6Linked to original sources
PubMed1986

Structural and functional features of a cell surface phosphoglycoprotein associated with tumorigenic phenotype in human fibroblast x HeLa cell hybrids.

Monoclonal antibodies have been raised against a dimeric cell surface antigen (p75/150) which is specifically associated with the tumorigenic phenotype in human fibroblast X HeLa hybrids. During biosynthesis, a precursor molecule (p70/140), was associated with microsomal membranes in vivo but possessed no detectable cytoplasmic domains. At this stage, each p70 monomer contained 3 "high-mannose" type N-linked glycans which were subsequently processed into endoglycosidase H-insensitive complex oligosaccharides on the mature cell surface forms. Cleavage of this cell surface form with endoglycosidase F yielded non-N-glycosylated polypeptides of Mr = 60,000/120,000. All the monoclonal antibodies identified similar non-N-glycosylated polypeptides in cells grown in the presence of tunicamycin. p75/150 could be weakly labeled with [3H]palmitic or myristic acid. In vivo, p75/150 was found to be phosphorylated on serine residues. Immunoprecipitates of p75/150 from HeLa or tumorigenic hybrid cell lysates exhibited protein kinase activity in vitro, which phosphorylated p75/150 itself, also on serine residues. We were unable to detect this kinase activity in normal fibroblasts and in the nontumorigenic hybrid cells. Furthermore, we were unable to detect p75/150 or its precursors by either cell surface labeling, metabolic labeling, or Western blotting in nontumorigenic cell hybrids; p75/150 thus represents a tumor-specific marker in this system. Tryptic peptides of highly purified p75/150 have been generated, but their amino acid sequences did not reveal any significant homology with previously described proteins.

Amino Acid Sequence↗
PubMed1986

Co-ordinate expression of BI.3C5 and HLA-DR antigens on haemopoietic progenitors from chronic myeloid leukaemia.

Haemopoietic cells isolated from the peripheral blood of patients with chronic myeloid leukaemia (CML), have been extensively purified and enriched using either Percoll density gradients or Percoll density gradients combined with elutriation. The quantitative expression of the BI.3C5 associated antigen and the co-expression of BI.3C5 and HLA-DR antigens on these two populations has been studied using either single or simultaneous two colour FACS sorting, following by in-vitro culture for single and multilineage haemopoietic progenitors thus obtained. The data show that the CFU-GEMM are always found in the most strongly BI.3C5 positive fraction, irrespective of the separation procedure and that the bulk of the CFU-GEMM co-express BI.3C5 and HLA-DR. The cell types initiating these CFU-GEMM are morphologically immature blasts. The more mature cells of the myelomonocytic and erythroid lineages forming single lineage colony types show variable BI.3C5 expression, although most are HLA-DR positive. Such enriched populations of malignant progenitors could provide a useful source of material to study both gene expression and the molecular mechanisms underlying malignant transformation.

Antibodies, Monoclonal↗
PubMed1986

Treatment of acute lymphoblastic leukaemia in adults.

Between 1972 and 1982, 112 consecutive previously untreated adults (aged 15-69 years, median 26) commenced therapy for acute lymphoblastic leukaemia (ALL) at St Bartholomew's Hospital. The first 63 patients entered into the study received initial treatment which comprised four cycles of adriamycin and vincristine, prednisolone and L-asparaginase with the first cycle (OPAL). In 1978, six cycles were given, with escalating doses of adriamycin and cyclophosphamide from cycle 3 (HEAV'D). Central nervous system (CNS) prophylaxis incorporated intrathecal methotrexate and cytosine arabinoside with cranial irradiation. Maintenance chemotherapy consisted of 6-mercaptopurine, cyclophosphamide and methotrexate for 3 years. Results obtained with the OPAL and HEAV'D regimens were not significantly different. The overall complete remission (CR) rate was 66% (73/111), factors correlating unfavourably with achievement of CR being advanced age (P less than 0.001) and L3 morphology/B-ALL immunophenotype (P less than 0.01). Fifty-three patients have relapsed, the bone marrow being the primary site in 43. Extramedullary relapse alone occurred in 10 (seven CNS, two testicular and one skin). Only three of the 64 patients who had complete CNS prophylaxis subsequently relapsed in the CNS as an isolated site. One patient died in CR, 19 remain in continuous CR between 2.5 and 10.5 years. The median duration of remission of the 73 patients who achieved CR was 18.5 months, factors correlating favourably with duration of CR being low blast cell count at presentation (P less than 0.002) and common ALL immunophenotype (P less than 0.04). Twenty-four patients remain alive, with a median survival of all patients of 18 months. Long-term survival is possible for approximately 20% of adults with ALL treated relatively intensively.

Acute Disease↗
PubMed1986

Clonal rearrangement and expression of the T cell receptor beta gene and involvement of the breakpoint cluster region in blast crisis of CGL.

A case of lymphoid blast crisis of Ph1-positive CGL is described in which the blast cells had an immature T cell phenotype, clonal rearrangement and expression of the T cell receptor beta gene, and a rearrangement of the breakpoint cluster region (bcr) on chromosome 22. This case therefore provides definite evidence for transformation involving a common myeloid-T lineage progenitor, penetrance of the Ph1 molecular alteration into the T cell lineage, and clonal selection in blast crisis at the level of a committed T lineage precursor.

Chromosome Mapping↗
PubMed1986

Lineage promiscuity in hemopoietic differentiation and leukemia.

An increasing number of reports document instances in which individual leukemic cells coexpress markers normally believed to be restricted to a single lineage. This has been interpreted by McCulloch and colleagues as aberrant programming or lineage infidelity and contrasts with earlier suggestions that lineage fidelity of gene expression was usually maintained in leukemia. We argue that several examples of infidelity are suspect on technical grounds, whereas others are bona fide and require explanation, eg, partial rearrangements and expression of Ig heavy-chain and/or T cell receptor genes in inappropriate cells and terminal deoxynucleotidyl transferase in leukemic myeloblasts. Individual examples of truly aberrant gene expression may well occur in leukemia but with insufficient regularity to be of general significance. We suggest that verifiable and consistent examples of apparent lineage infidelity do not reflect genetic misprogramming but rather the existence of a transient phase of limited promiscuity of gene expression occurring in normal biopotential or multipotential progenitors and able to be preserved as a relic in leukemic blast cell populations that are in maturation arrest. This alternative explanation has interesting implications for mechanisms of hematopoietic differentiation and leads to some testable predictions.

Animals↗
PubMed1986

Divergent molecular phenotypes of KG1 and KG1a myeloid cell lines.

The cell line KG1 derived from a patient with erythroleukemia in myeloblastic relapse has the composite phenotype and functional repertoire of myeloblasts. In marked contrast, its subline KG1a has lost myeloid features, acquired new karyotypic markers, and has three characteristics associated with immature T cells: low-level expression of the T cell receptor beta mRNA (but not alpha) transcribed from a germline gene; high-level expression of T3 delta mRNA and intracellular, but not cell surface, T3 protein; and expression of the CD7/gp40 T cell-associated membrane antigen. Both KG1 and KG1a transcribe unrearranged IgH genes. These data suggest that either the KG1 cell line was derived from a common myeloid-lymphoid progenitor or that the KG1a subline phenotype is aberrant.

Antibodies, Monoclonal↗
PubMed1985

Expression of Burkitt lymphoma-associated antigen (defined by the monoclonal antibody 38.13) on both normal and malignant germinal-centre B cells.

Monoclonal antibody 38.13 was raised against the Burkitt lymphoma cell line Daudi and has been previously shown to recognize a globotriaosylceramide (Pk) determinant expressed selectively on Burkitt and a few other B-cell lymphomas. We report here that 38.13 binds to a subset of normal B lymphocytes in germinal centres of secondary lymphoid follicles as well as to blood vessels. In malignant populations equivalent to various developmental compartments of the B-cell lineage, only those with a follicular phenotype express the Pk determinant at detectable levels. The expression of this tumour-associated antigen, in common with many others, is therefore regulated in concert with cell lineage and maturation status.

Animals↗
PubMed1985

Contribution of immunophenotype to the classification and differential diagnosis of acute leukaemia.

The diagnostic value of a panel of monoclonal antibodies was assessed in 100 consecutive patients with acute leukaemia. 97 patients were clearly phenotyped. Clinical and haematological feedback showed that the immunological data made a critical contribution to the final haematological diagnosis in 19 patients and provided useful confirmatory data in another 78. Immunophenotype also provided the basis for a subset classification of known prognostic relevance to acute lymphoblastic leukaemia (ALL). Immunophenotype and haematological findings conflicted in 2 cases, and 3 cases were unclassifiable with the antibody panel. In these difficult cases leukaemic-cell DNA was investigated for immunoglobulin gene rearrangement. Immunophenotyping with selective probes may be used in conjunction with other laboratory analyses (eg, karyotyping) in the routine investigation of patients with acute leukaemia.

Acute Disease↗
PubMed1985

Chromosome mapping of cell membrane antigens expressed on activated B cells.

Hybrids formed by fusion of either human acute lymphoblastic or chronic lymphocytic leukemia cells and the mouse myeloma P3.X63.Ag8/653 have been used to show that the expression of two cell surface antigens, Bp37 and p76, associated with B cell activation and detected by the monoclonal antibodies BB1 and BB2, respectively, segregate with human chromosomes 12 and 19, respectively. Another antigen expressed on activated B cells (p24) also maps to chromosome 12 (Katz et al., Eur. J. Immunol. 1984. 13: 1008) which is of interest in the light of the frequent involvement of this chromosome in certain B cell leukemias and lymphomas.

Animals↗
PubMed1985

Identification of a membrane glycoprotein associated with haemopoietic progenitor cells.

A monoclonal antibody (3C5) is described which selectively binds to progenitor cell populations in human bone marrow and foetal liver. Mature, lymphoid (T,B) colony forming cells do not express the antigen. The antibody identifies a cell surface glycoprotein of mol. wt approximately 100,000 which might have an important regulatory role in early haemopoietic differentiation.

Animals↗
PubMed1985

Monosomy 7 and multipotential stem cell transformation.

Monosomy 7 was the sole karyotypic abnormality seen in a case of biphenotypic leukaemia involving both the myeloid and lymphoid lineages and in a case of de novo ALL undergoing a phenotypic shift to acute myeloid leukaemia at relapse. These observations suggest that monosomy 7 can be associated with transformation of a common lymphoid-myeloid progenitor cell.

Aged↗
PubMed1985

Selective expression of class-II MHC antigens during hemopoietic differentiation.

Human multipotential or "mixed" bone marrow colony-forming cells and lineage-restricted colony-forming progenitors have been analyzed by cell sorting (FACS) using a series of monoclonal antibodies. The latter all react with monomorphic class-II MHC glycoprotein determinants but differ in their reactivity or cross-reactivity with products of different loci, i.e., SB (DP), DC (DQ), DR. The results confirm that very few progenitor cells detectably express DC. Anti-DR monoclonals varied in their reactivity with progenitor cells. The majority of progenitors in all lineage categories express determinants that are shared or cross-reactive between DR and SB while fewer progenitors can be shown to bind antibodies specific for DR or SB.

Antibodies, Monoclonal↗