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A T Look

Publications and source records attributed to A T Look.

At least 145 records · Page 8Linked to original sources
PubMed1990

Cytogenetics of pre-B-cell acute lymphoblastic leukemia with emphasis on prognostic implications of the t(1;19).

In earlier studies of the cytogenetic characteristics of leukemic lymphoblasts from children with pre-B-cell acute lymphoblastic leukemia (ALL), we concluded that certain chromosomal abnormalities explain, in part, the increased presence of high-risk features at diagnosis and the less favorable response to therapy among patients with this immunologic subclass of ALL. With extended follow-up and a larger patient population, we have further evaluated the biologic and clinical aspects of pre-B leukemia. Of 686 cases of ALL with adequate immunophenotyping, 150 were classified as pre-B cell. Seventy-seven (69%) of the 112 pre-B cases with fully banded karyotypes had a translocation. The t(1;19) accounted for 28 (25%) of these pre-B cases and 31 (6.5%) of all 480 consecutively banded ALL cases. Three (2.6%) of the pre-B cases had a novel dicentric (7;9)(p1?3;p11) translocation. A t(9;22)(q34;q11) and a t(4;11)(q21;q23) were observed in seven (6%) and three (2.6%) of the cases, respectively. Within the pre-B subgroup, comparison of t(1;19) cases (n = 28) with those having other translocations (n = 49) or no identifiable translocations (n = 35) indicated that higher leukocyte counts (P = .002), absence of DNA indexes greater than 1.16 (P = .02), higher serum lactate dehydrogenase levels (P less than .0001), and a higher frequency of nonwhite race (P = .006) were significantly related to the t(1;19). Both the t(1;19) and other chromosomal translocations were associated with an adverse prognosis in the subset of patients treated from 1979 to 1984 (Total Therapy study X). In a more recent and more intensive chemotherapy program (Total Therapy study XI), neither the t(1;19) nor other chromosomal translocations has conferred an inferior outcome, suggesting that effective treatment can offset the negative impact of chromosomal rearrangements in cases of childhood pre-B ALL.

Child↗
PubMed1990

Prognostic significance of CD34 expression in childhood B-precursor acute lymphocytic leukemia: a Pediatric Oncology Group study.

We studied the blasts from 795 children greater than 1 year of age with newly diagnosed, untreated B-precursor acute lymphoblastic leukemia (ALL) for expression of the hematopoietic stem cell-associated antigen CD34. All cases were confirmed as B-lineage lymphoblastic leukemia by virtue of expression of CD19 and/or CD22, lack of T-cell antigens, and lack of surface-membrane immunoglobulin (Ig). The CD34 antigen was present in at least 10% of blast cells in 587 (73.8%) of the patients. There was no significant difference in presenting clinical characteristics between CD34+ and CD34- patients save for an increased incidence of CNS involvement at diagnosis in the latter. Patients with CD34+ leukemia were more likely to have blasts expressing CD22, CD9, and CD13 antigens but were less likely to coexpress CD20. Patients with pre-B (cytoplasmic mu) ALL were significantly more likely to lack CD34 on their blasts, while children with hyperdiploid ALL were more likely to be CD34+. Although remission induction rates were not significantly different between patients with CD34+ and CD34-ALL (P = .23), event-free survival was shorter for patients with CD34- leukemia (P = .0014). Even though CD34 expression was associated with certain other known prognostically favorable variables including hyperdiploidy and lack of cytoplasmic Ig, it had an independent favorable effect on treatment outcome, even after adjusting for competing prognostic factors.

Antigens, CD↗
PubMed1990

Presenting features and treatment outcome of adolescents with acute lymphoblastic leukemia.

Adolescents had lower rates of remission induction and shorter event-free survival than younger children in this study of consecutively treated patients with acute lymphoblastic leukemia (ALL). When compared to the younger patients (ages 1-9 years; n = 995), adolescents (ages 10-21 years; n = 338) were significantly more likely to have adverse prognostic features, including T cell phenotype, L2 blast cell morphology, higher serum lactate dehydrogenase level, higher leukocyte count, leukemic cell DNA index less than 1.16, and ploidy other than hyperdiploidy greater than 50. Within the adolescent group, outcome was worse for those older than 15 years. The increased frequency of unfavorable clinical and biologic features undoubtedly accounts in part for the poorer prognosis of adolescents with ALL. However, the independent prognostic significance of age greater than or equal to 10 years suggests that as yet unknown factors contribute to treatment failure in adolescent patients.

Adolescent↗
PubMed1989

Amplification of the gli gene in childhood sarcomas.

The gli gene, originally identified by its amplified copy number in cells from a human malignant glioma, has a predicted translation product that contains five tandem DNA-binding zinc finger motifs related to those of Krüppel, a developmentally important Drosophila segmentation gene. Because of the potential importance of overproduction of this protein in neoplastic development, we examined DNAs from 29 cases of childhood sarcoma for evidence of amplification of the gli gene. In one of the 13 rhabdomyosarcomas studied, genomic DNA restriction fragments containing the gli gene were amplified approximately 30-fold, and expression of the 4.0-kilobase gli mRNA transcript was identified. The tumor with gli gene amplification lacked the usual histological features of alveolar or embryonal rhabdomyosarcoma; however, ultrastructural analysis of tumor cells established in culture revealed attenuated sarcomeres, resembling those found in primitive rhabdomyoblasts. Cytogenetic analysis of this cell line disclosed double-minute chromatin bodies, with no apparent rearrangements in the region of the gli locus on the long arm of chromosome 12, bands q13 to q14.3. A 15-fold level of gli amplification and gli mRNA transcripts were also detected in an established cell line from a patient with a rare form of osteosarcoma characterized by multipotential histological features. A similar level of gli gene amplification was observed in cryopreserved primary tumor cells from this patient, confirming that gene amplification took place during tumor development and not during in vitro cell culture. Amplified gli sequences were cytogenetically localized by in situ hybridization to a homogeneously staining region contained on a derivative chromosome 7. Of eight osteosarcomas and seven Ewing's sarcomas with typical histopathological features, none had detectable rearrangements or amplification of gli sequences. Thus, gli gene amplification in childhood sarcomas appears restricted to tumors with primitive histopathological features, perhaps reflecting overproduction of a gene product able to influence gene expression during early mesenchymal cell development.

Adolescent↗
PubMed1989

Prognostic importance of structural chromosomal abnormalities in children with hyperdiploid (greater than 50 chromosomes) acute lymphoblastic leukemia.

Approximately one fourth of children with newly diagnosed acute lymphoblastic leukemia (ALL) have hyperdiploid (greater than 50 chromosomes) blasts and a relatively favorable prognosis. Nonetheless, a substantial proportion of these patients fail therapy. We studied 138 children (70 male, 68 female) with hyperdiploid greater than 50 ALL to assess initial clinical and cytogenetic features that might predict treatment failure. In 85 of these cases (62%), structural chromosomal abnormalities were also present; clinical and laboratory features in this group did not differ from those of the 53 cases with only numeric abnormalities. However, of the 28 failures seen at a median follow-up of 4 years, 22 occurred in cases with structural chromosomal abnormalities (P = .03 by Breslow test). In a multivariate analysis, only the presence of structural chromosomal abnormalities and male gender were independently associated with treatment failure. Structural chromosomal abnormalities in cases of ALL with greater than 50 chromosomes may define a biologically different form of leukemia characterized by increased likelihood of drug resistance.

Adolescent↗
PubMed1989

Monoclonal antibodies to the human CSF-1 receptor (c-fms proto-oncogene product) detect epitopes on normal mononuclear phagocytes and on human myeloid leukemic blast cells.

The first monoclonal antibodies (MoAbs) to epitopes in the extracellular domain of the human c-fms proto-oncogene product (receptor for the macrophage colony stimulating factor, CSF-1) were used with flow cytometric techniques to study receptor expression on normal human peripheral blood monocytes, bone marrow cells, and leukemic blasts. On normal cells CSF-1 receptors were restricted in their expression to cells of the mononuclear phagocyte lineage. CSF-1 receptors were detected on leukemic blasts from 15 (30%) of 50 children with acute myeloid leukemia, compared with four (15%) of 26 adults. By contrast, detectable CSF-1 receptors were uniformly absent on blasts from 19 children with acute lymphoblastic leukemia. CSF-1 receptors on normal monocytes and myeloid leukemia cells could be induced to downmodulate by incubation with either human recombinant CSF-1 or phorbol esters, confirming that the receptors had functional ligand-binding sites and responded to transmodulation by inducers of protein kinase C. The numbers of receptors per cell and the percentage of positive cases were highest for leukemic blasts with cytochemical and morphological features of monocytes. However, CSF-1 receptors were also detected on a subset of leukemic blast cells with features of granulocytic differentiation (FAB subtypes M1 through M3). Southern blotting analyses of DNA from 47 cases of acute myeloid leukemia demonstrated no rearrangements within the 32 kb of genomic sequences that contain CSF-1 receptor coding exons or in the 50 kb upstream of the first coding exon. Analysis of the upstream region of the c-fms locus revealed that sequences representing the terminal 112 untranslated nucleotides of c-fms mRNA map 26 kb 5' to the first coding exon, suggesting that at least one c-fms promoter is separated from the receptor coding sequences by a very long intron. Whereas expression of the CSF-1 receptor in myeloid leukemic blasts is not restricted to cells with monocytic characteristics, the apparently aberrant pattern of receptor synthesis in a subset of cases with granulocytic features appears not to be due to chromosomal rearrangements within 50 kb upstream of sequences encoding the receptor.

Antibodies, Monoclonal↗
PubMed1989

Closely linked loci on the long arm of chromosome 13 flank a specific 2;13 translocation breakpoint in childhood rhabdomyosarcoma.

A specific chromosomal translocation, t(2;13)(q35;q14), is present in tumor cells from about one-half of children with alveolar rhabdomyosarcoma, who generally have widely disseminated disease at diagnosis. Using a series of six DNA probes from five loci previously assigned to bands 13q12----q14, we have localized the translocation breakpoint on chromosome 13 by in situ hybridization. Each probe was used to examine metaphase spreads from two or more rhabdomyosarcoma cell lines that have the t(2;13), as well as from control lymphoblastoid cell metaphases. All six probes bound to chromosome 13q12----q14 in the control cell line, but showed no appreciable hybridization to other sites. With rhabdomyosarcoma metaphases, cDNA clones of the retinoblastoma susceptibility gene (RB1) and the esterase D gene (ESD), as well as the arbitrary genomic fragment 7D2 (D13S10), showed specific hybridization to the normal chromosome 13 and the der(2) marker, but not to the der(13). By contrast, the genomic fragments HU10 (D13S6) and 7F12 (D13S1) hybridized specifically to the normal chromosome 13 and the der(13), but not to the der(2). Thus, the breakpoint of this translocation lies distal to D13S6 and D13S1 and proximal to ESD, RB1, and D13S10. Our data indicate that the locus affected by the translocation breakpoint on chromosome 13, which we have termed RMS, is physically distinct from the RB1 locus and is, in fact, proximal to ESD, which others have placed at least 10(6) bp proximal to RB1. The consistent presence of the der(2) marker chromosome, coupled with occasional loss of the der(13), suggests that the RMS gene, or at least a critical component, moves to chromosome 2 in tumors with this translocation.

Cell Line↗
PubMed1989

Human myeloid plasma membrane glycoprotein CD13 (gp150) is identical to aminopeptidase N.

To determine the primary structure of CD13, a 150-kD cell surface glycoprotein originally identified on subsets of normal and malignant human myeloid cells, we isolated the complete sequences encoding the polypeptide in overlapping complementary DNA (cDNA) clones. The authenticity of our cDNA clones was demonstrated by the ability of the coding sequences, subcloned in a retroviral expression vector, to mediate expression of bona fide CD13 molecules at the surface of transfected mouse fibroblasts. The nucleotide sequence predicts a 967 amino acid integral membrane protein with a single, 24 amino acid hydrophobic segment near the amino terminus. Amino-terminal protein sequence analysis of CD13 molecules indicated that the hydrophobic segment is not cleaved, but rather serves as both a signal for membrane insertion and as a stable membrane-spanning segment. The remainder of the molecule consists of a large extracellular carboxyterminal domain, which contains a pentapeptide consensus sequence characteristic of members of the zinc-binding metalloprotease superfamily. Sequence comparisons with known enzymes of this class revealed that CD13 is identical to aminopeptidase N, a membrane-bound glycoprotein thought to be involved in the metabolism of regulatory peptides by diverse cell types, including small intestinal and renal tubular epithelial cells, macrophages, granulocytes, and synaptic membranes prepared from cells of the central nervous system.

Amino Acid Sequence↗
PubMed1988

Tandem linkage of human CSF-1 receptor (c-fms) and PDGF receptor genes.

A 5' untranslated exon of the human CSF-1 receptor gene (c-fms) is separated by a 26 kb intron from the 32 kb receptor coding sequences. Nucleotide sequence analysis of cloned genomic DNA revealed that the 3' end of the PDGF receptor gene is located less than 0.5 kb upstream from this exon. Similarities in chromosomal localization, organization, and encoded amino acid sequences suggest that the genes encoding the CSF-1 and PDGF receptors arose through duplication. The as yet unidentified c-fms promoter/enhancer sequences may be confined to the nucleotides separating the two genes or could potentially lie within the PDGF receptor gene itself.

Amino Acid Sequence↗
PubMed1988

Clinical importance of near-diploid tumor stem lines in patients with osteosarcoma of an extremity.

We determined the clinical value of flow-cytometric measurement of tumor-cell DNA content, which reflects the chromosome number (ploidy), in patients with osteosarcoma of an extremity. Hyperdiploid stem lines were identified in 25 of 26 tumor samples obtained at diagnosis from patients who did not have clinically overt metastases. Near-diploid tumor stem lines coexisted with hyperdiploid lines in 15 of these 25 cases; an isolated near-diploid line was present in the 26th case. All 26 patients underwent definitive surgery and then were treated uniformly with intensive adjuvant combination chemotherapy. Kaplan-Meier analysis of both relapse-free and overall survival times showed that the presence of a near-diploid tumor stem line was associated with improved outcome (P = 0.003 for each comparison). After a median follow-up time of three years, pulmonary metastases developed in only 2 patients in the group with near-diploid lines, in contrast to 7 of the 10 with hyperdiploid lines exclusively. Near diploidy remained significantly associated with improved relapse-free survival after adjustment for the influence of age, the only clinical variable that showed prognostic strength in this analysis (P less than 0.01; relative risk, 0.08; 95 percent confidence interval, 0.02 to 0.48). Our findings demonstrate the usefulness of flow-cytometric determination of tumor-cell ploidy for predicting the sensitivity of histologically high-grade osteosarcoma to chemotherapeutic agents. Patients with a near-diploid tumor stem line can be expected to respond favorably to adjuvant chemotherapy as used in this study, whereas those with only hyperdiploid lines should be considered as candidates for alternative therapy.

Adolescent↗
PubMed1988

High-dose methotrexate improves clinical outcome in children with acute lymphoblastic leukemia: St. Jude Total Therapy Study X.

High-dose methotrexate (HDMTX, 1,000 mg/m2) and cranial irradiation/sequential chemotherapy (RTSC) were compared for ability to extend complete remission durations in children with acute lymphoblastic leukemia (ALL). Three hundred thirty patients were enrolled in the study, according to our criteria for standard-risk ALL: a leukocyte count less than 100 X 10(9)/L, no mediastinal mass, no leukemic involvement of the central nervous system (CNS), and blast cells lacking sheep erythrocyte receptors and surface immunoglobulin. Prednisone-vincristine-asparaginase induced complete remissions in 95% of the patients, who were then randomized to receive either HDMTX (n = 154) or RTSC (n = 155). HDMTX was administered with intrathecal MTX for the first 3 weeks following remission induction, and then every 6 weeks with daily mercaptopurine (MP) and weekly oral MTX for a total of 18 months. The RTSC regimen consisted of 1,800 cGy cranial irradiation and intrathecal MTX for 3 weeks, followed by MP/MTX, cyclophosphamide/doxorubicin, and teniposide/cytarabine administered sequentially over 18 months. The final 12 months of treatment for both groups was MP and oral MTX; all patients received intrathecal MTX every 12 weeks. With a median follow-up of 5 years, complete remission durations have been significantly longer among children treated with HDMTX, compared with RTSC (P = .049) or historical institutional control regimens (P = .002). Approximately 67% of the patients receiving HDMTX and 56% of those receiving RTSC are expected to be in continuous complete remission at 4 years. Overall, isolated CNS relapse rates were similar (P = .17) in the two treatment groups, although by newer risk criteria cranial irradiation could be expected to provide better protection in patients with an unfavorable prognosis. These findings indicate that addition of intermittent HDMTX infusions to conventional chemotherapy is an effective method for extending complete remissions in children with ALL.

Child↗
PubMed1988

The cytogenetics of childhood leukemia: clinical and biologic implications.

Cytogenetic studies have revealed a broad spectrum of abnormalities in the chromosomal make-up of human leukemic cells. These abnormalities are acquired during the process of malignant transformation within the neoplastic clone and reflect the genetic lesions and ablations that have occurred. Because cytogenetic abnormalities are tightly linked to the molecular events that lead to leukemogenesis, it is not surprising that these features correlate with immunophenotypic and morphologic features of the leukemic cells, as well as with the clinical characteristics of children at diagnosis and their responsiveness to therapy. Molecular analysis of the disordered structure or disrupted regulation of genes located at critical chromosomal breakpoints in leukemic cells should continue to provide important insight into normal and aberrant hematopoietic cell function.

Acute Disease↗
PubMed1988

Intensified chemotherapy for childhood lymphoblastic leukemia: modifications and results of induction treatment in St. Jude Study XI.

The value of intensified chemotherapy for improving event-free survival rates in childhood lymphoblastic leukemia (ALL) is now widely accepted among leukemia therapists. Still to be determined are (1) the optimal method of intensification, (2) the subset or subsets of patients for whom such treatment may be excessive, and (3) whether or not cure rates in ALL can be further improved by alternative approaches to intensification. St. Jude Total Therapy Study XI, based on predictions of the Goldie-Coldmand model of drug resistance, addresses some of these questions by use of rotational "non-cross-resistant" drug pairs throughout the course of therapy. A new method of risk classification has been developed to refine distinctions among prognostic subgroups, especially to identify patients with biologically unfavorable ALL. Unacceptable toxicity noted in the first 134 children enrolled in this study led to two protocol modifications. One hundred thirty-two patients have been treated subsequently without undue toxicity. The treatment is now being delivered safely. Our early experience with this regimen demonstrates some of the hazards of intensive multidrug combination treatment, but gains in leukemia control appear to justify this approach.

Antineoplastic Agents↗
PubMed1988

Molecular cloning, expression, and chromosomal localization of a human gene encoding the CD33 myeloid differentiation antigen.

Monoclonal antibodies of the CD33 cluster group recognize a 67-kilodalton (Kd) protein, designated p67, expressed on the surface of normal human myeloid progenitors and leukemic cells from most patients with acute myelogenous leukemia. The human gene encoding p67 was isolated in a mouse genetic background after DNA-mediated gene transfer and fluorescence-activated cell sorting (FACS) for transformants that bound the monoclonal antibody MY9. After three serial rounds of gene transfer and cell sorting, multiple independently derived tertiary mouse cell transformants were obtained that expressed p67. Southern blot analysis revealed that these transformants shared restriction fragments containing highly reiterated human DNA sequences. Two shared EcoRI fragments of 3.3-kilobase (kb) and 9.5-kb pairs were molecularly cloned into bacteriophage vectors. A subsegment of the 3.3-kb fragment lacking repeated sequences was then used as a unique sequence probe to isolate two independent cosmid clones. Cells transfected with DNA from both cosmid clones bound MY9, and the human p67 protein was demonstrated by immunoprecipitation. NFS mice inoculated with a mouse cell transformant coexpressing p67 and the v-fms oncogene product produced antisera that specifically immunoprecipitated p67 from human leukemic cell lines, mouse cell transformants, and mouse cells transfected with the biologically active cosmid clones. The human p67 locus was previously assigned to chromosome 19 by screening a panel of rodent X human somatic cell hybrids with the unique sequence probe. The gene was sublocalized to the q13.3 region of chromosome 19 by in situ hybridization. RNA transcripts of approximately 1.6 kb and 1.4 kb were identified in polyadenylated RNA from human myeloid leukemia cell lines using a probe from the genomic locus. Manipulation of the cloned p67 gene may provide insight into the function of its product and mechanisms regulating its expression.

Animals↗