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Biomedical subjects

C R Bartram

Publications and source records attributed to C R Bartram.

At least 91 records · Page 5Linked to original sources
PubMed1995

Therapy with OKT3 monoclonal antibody in refractory T cell acute lymphoblastic leukemia induces interleukin-2 responsiveness.

Administration of cytokines to patients with leukemia or lymphoma may recruit dormant malignant cells into cell cycle and thus make them more susceptible to chemotherapy. We treated a patient with refractory T cell acute lymphoblastic leukemia (ALL) with OKT3 monoclonal antibody and observed a dramatic but transient decrease of lymphoblasts. The T ALL cells were rather mature by morphology and immunophenotyping, expressing CD7, CD4, CD8 and CD3 surface antigens and nuclear TdT. Cytogenetic analysis revealed inversion of chromosome 14(q11q32.1). A total of 500 mg OKT3 (maximum dose 50 mg/day) was given. A decrease of lymphoblasts in the blood and a reduction of spleen size was observed. Complement levels dropped remarkably. Despite increasing serum levels of tumor necrosis factor, treatment was well tolerated overall. CD3 therapy induced strong IL-2 responsiveness of the lymphoblasts. Thus, OKT3 antibody treatment not only significantly decreased CD3-positive tumor cells, but also induced IL-2-mediated proliferation. This may also allow sequential application of CD3 and IL-2 to render certain T cell tumors more susceptible to chemotherapy.

Adult↗
PubMed1994

Confirmation of the localization of the human recombination activating gene 1 (RAG1) to chromosome 11p13.

The human recombination activating gene 1 (RAG1) has previously been mapped to chromosomes 14q and 11p. Here we confirm the chromosome 11 assignment by two independent approaches: autoradiographic and fluorescence in situ hybridization to metaphase spreads and analysis of human-hamster somatic cell hybrid DNA by the polymerase chain reaction (PCR) and Southern blotting. Our results unequivocally localize RAG1 to 11p13.

Animals↗
PubMed1994

The acute lymphoblastic leukaemia cell line SEM with t(4;11) chromosomal rearrangement is biphenotypic and responsive to interleukin-7.

A cell line, designated SEM, was established from the peripheral blood of a 5-year-old girl in relapse with acute lymphoblastic leukaemia (ALL). Both the lymphoblasts of the patient and the cells of the cell line SEM showed the t(4;11) chromosomal rearrangement. The analysis of the immunophenotype of the SEM cell line revealed the B-cell differentiation antigens CD19, CD22 and CDw75 in the absence of CD20, CD24 and immunoglobulin expression. Besides B-lineage antigens, SEM cells were positive for the myeloid antigens CD13, CD15, CD33 and CDw65. Immunogenotypic analysis of SEM cells showed a monoclonal rearrangement of immunoglobulin heavy-chain (IgH). T-cell receptor (TCR) gamma and delta genes. Addition of interleukin (IL)-7 promoted the growth of the patient's lymphoblasts in culture and enhanced the proliferation of SEM cells. The SEM cells also express messenger RNA (mRNA) for the IL-7 receptor (IL-7R), but no evidence for autocrine production of IL-7 by the cell line was found. Addition of IL-4, tumour necrosis factor (TNF)-alpha, interferon (IFN)-alpha, or IFN-gamma resulted in a profound inhibition of SEM growth. Thus, these cytokines may have important growth regulatory activities for biphenotypic leukaemic ALL cells.

Antigens, CD↗
PubMed1994

t(5;14)(q33-34;q11), a new recurring cytogenetic abnormality in childhood acute leukemia.

A novel translocation, t(5;14)(q33-34;q11), was identified in the leukemic cells of four children presenting with acute lymphoblastic leukemia (ALL). The patients were 14 months, 2 years, 10 years, and 12 years old; each presented with one or more features of bulky disease, including lymphadenopathy, organomegaly or a mediastinal mass. The leukemic blasts were B lineage in two cases and T lineage in two cases. The patients with B-lineage ALL remain in continuous remission at 22 and 19 months following diagnosis. One patient with T-lineage ALL relapsed 6 months after diagnosis. The other patient with T-lineage ALL developed acute myelocytic leukemia (AML) 17 months after diagnosis; t(5;14)(q33-34;q11) was present in both the lymphoblasts at diagnosis and the myeloblasts at relapse, consistent with a lineage switch from ALL to AML. Rearrangement of the T-cell receptor delta chain (TCRD) gene at 14q11 was demonstrated in the three cases studied, suggesting its involvement in the pathogenesis of these leukemias by alteration of the structure or expression of an unidentified gene(s) on the long arm of chromosome 5.

Child↗
PubMed1993

Analysis of p53 mutations in a large series of lymphoid hematologic malignancies of childhood.

p53 mutations are found in a wide variety of cancers, including hematologic malignancies. These alterations apparently contribute to development of the malignant phenotype. We analyzed a large series of lymphoid (330 cases) and a smaller series of myeloid (29 cases) malignancies of childhood for p53 mutations by single-strand conformational polymorphism (SSCP) following polymerase chain reaction. Samples with abnormal SSCP were reamplified and analyzed by direct sequencing method. p53 mutations were detected within the known mutational hotspots (exons 5 to 8) in 8 of 330 lymphoid malignancies, and in none of 29 myeloid malignancies, showing that the frequency of p53 mutations in childhood lymphoid malignancies was very low (8 of 330 cases [2%]). Four of these patients had very aggressive, fatal acute lymphocytic leukemia (ALL). None of 13 infants and none of 48 patients with T-lineage leukemia had detectable p53 mutations in their ALL cells. Exceptionally, p53 mutations were comparatively frequent in a small sample of B-cell non-Hodgkin's lymphomas (2 of 8 cases). Mutations were detected in samples from two patients with ALL at relapse; these were not detected in samples at initial diagnosis from the same patients, suggesting that p53 mutations may be associated with progression to a more malignant phenotype. Seven of eight alterations of p53 were missense mutations, and seven of eight samples may be heterozygous for the mutant p53, indicating that p53 protein may act in a dominant negative fashion.

Adolescent↗
PubMed1993

Mutation of the p53 gene in neuroblastoma and its relationship with N-myc amplification.

Mutation of the p53 tumor suppressor gene frequently occurs in a variety of tumors including lung, breast, gastrointestinal, and brain, as well as lymphomas-leukemias. Neuroblastoma, one of the most common solid tumors in childhood, often has amplification of the N-myc gene. We examined for mutations of the p53 tumor suppressor gene by single-strand conformational polymorphism using polymerase chain reaction products and direct sequencing method in neuroblastoma; in addition, we assessed the relationship between p53 mutation and N-myc gene amplification in the disease. Of 86 DNA samples from patients with neuroblastoma, two mutations (2%) were found in the coding region of the p53 gene. Each mutation caused a substitution of amino acid residues. One mutation was located in exon 5, and another was in exon 6. N-myc gene was amplified in 26% of the samples. No p53 mutations were found in neuroblastoma samples with N-myc amplification. In the two individuals, p53 mutations appeared as their disease became more progressive. The neurofibromatosis 1 (NF1) gene is frequently abnormal in another neural disorder, neurofibromatosis type 1; in addition, a potential mutational hot spot of NF1 at lysine at codon 1423 has been identified in several types of tumors. Using single-strand conformational polymorphism, we were unable to detect an abnormality in this region of NF1 in 50 samples of neuroblastoma. The data suggest that p53 mutations occasionally are associated with progression of neuroblastomas, and tumorigenetic influences of mutant p53 may differ from those of N-myc.

Gene Amplification↗
PubMed1993

BCR-ABL rearrangement in a child with acute myelogenous leukaemia without a Philadelphia chromosome.

We describe a BCR/ABL rearrangement positive but Philadelphia chromosome negative status in a 9-year-old boy suffering from an acute myelogenous leukaemia (AML). This case was detected in a prospective PCR screening procedure including 21 children with newly diagnosed AML and 150 children with acute lymphoblastic leukaemia (ALL). We found a 5.4% incidence of BCR/ABL rearrangement positive cases in pre-B and c-ALL in childhood.

Child↗
PubMed1993

Expression of identical E2A/PBX1 fusion transcripts occurs in both pre-B and early pre-B immunological subtypes of childhood acute lymphoblastic leukemia.

The translocation t(1;19)(q23;p13) in pediatric patients with acute lymphoblastic leukemia (ALL) was demonstrated in early reports to result in a consistent fusion between the E2A and PBX1 gene sequences and in the expression of a uniform, chimeric E2A/PBX1 mRNA with transforming potential. More recent observations suggested that cytogenetically identical t(1;19) translocations can result in the transcription of different mRNA species and that expression of the E2A/PBX1 message may be restricted to patients with the t(1;19) who display a pre-B phenotype of ALL. To further assess the correlation between the immunologic subtypes of the disease and specific genetic alterations, we have performed cytogenetic and molecular analyses in 221 children with B-lineage ALL. Expression of the chimeric E2A/PBX1 message was detected in 21 patients. Out of 14 patients, in whom cytoplasmic immunoglobulin (cig) analyses were available, no less than four had a cig- B-cell precursor ALL, whereas 10 displayed a cig+ B-ALL immunophenotype. These findings are at variance with a recent report in which expression of the E2A/PBX1 message was linked exclusively to a subset of patients who displayed a cig+ pre-B-cell precursor phenotype of ALL. In seven cases diagnosed before 1986, cig analyses were not available, and consequently E2A/PBX1 expression could not be correlated to a particular immunological subtype of B-cell precursor ALL. Our results have important implications for the detection of residual disease in pediatric patients where expression of the typical E2A/PBX1 mRNA may occur both in cig+ (pre-B) and cig- (early pre-B) immunologic subtypes of ALL.

Child↗
PubMed1993

Mutations within the FLR exon of NF1 are rare in myelodysplastic syndromes and acute myelocytic leukemias.

A mutational hotspot in the neurofibromatosis 1 (NF1) gene has recently emerged from the analysis of different malignancies including one patient with myelodysplastic syndrome (MDS). In these cases, Lys 1423 in the GTPase-activating protein (GAP)-related domain of NF1 is substituted which causes a significant reduction of intrinsic GAP activity. We studied 57 MDS patients and 27 cases of acute myelocytic leukemia (AML) for mutations at codon 1423 in the so-called FLR exon of NF1 by an assay based on restriction enzyme digestion. We investigated the entire FLR exon and its flanking intron sequences using single-strand conformation polymorphism (SSCP) analysis of polymerase chain reaction (PCR) products and sequencing. None of the cases exhibited a codon 1423 mutation. However, a patient with chronic myelomonocytic leukemia (CMML) showed a 3 bp deletion within the splice acceptor region in front of the FLR exon. These data suggest that NF1 exon FLR mutations contribute infrequently to the development of MDS and AML.

Acute Disease↗
PubMed1993

SIL-TAL1 deletion in T-cell acute lymphoblastic leukemia.

The TAL1 gene on chromosome 1 encodes a hematopoietic transcription factor. Disruption of TAL1 via chromosomal translocation or a site-specific deletion has been reported in up to 30% of T-cell acute lymphoblastic leukemias (T-ALL). Here we used a polymerase chain reaction (PCR) assay to identify the 90 kb SIL-TAL1 deletion in a group of 19 cutaneous T-cell lymphomas and a series of 142 T-ALL patients (76 children, 66 adults). While none of the T-cell lymphoma exhibited a SIL-TAL1 recombination, seven T-ALL cases showed a type d1 and two patients a type d2 deletion. Of pediatric T-ALL, 9% (7/76) and of adult patients only 3% (2/66) were characterized by this genomic lesion. The deletion correlated with commitment to the T-cell receptor (TCR) alpha beta lineage, but lacked association with a distinct maturation stage. Sequence analysis of SIL-TAL1 breakpoints revealed marked heterogeneity at the junctional region among the nine patients due to random deletion and insertion of N-region nucleotides or templated P-nucleotide addition mediated via illegitimate V(D)J recombinase action. Clonospecific oligomer probes in conjunction with PCR allowed the detection of minimal residual disease in one out of four patients monitored during complete hematologic remission.

Adolescent↗
PubMed1993

Molecular evidence of minimal residual disease after treatment for leukaemia and lymphoma: an updated meeting report and review.

The very rapid development in the last few years of techniques based on use of the polymerase chain reaction (PCR) for characterizing molecular lesions in leukaemia and lymphoma now offers the opportunity for monitoring residual disease at a sensitivity of one malignant cell in 10(5) or 10(6) normal cells. Maximal specificity is presumably achieved when the DNA sequences amplified are truly leukaemia-specific, such as BCR/ABL in chronic myelogenous leukemia, RARA PML/RARA in t(15;17) acute myelogenous leukemia, DEK/CAN in t(6;9) AML, PBX1/E2A in t(1;19) acute lymphoblastic leukemia (ALL), or TAL-1 deletions in other T-ALLs. Comparable sensitivity may be achieved by using immunoglobulin heavy chain (IGH) and T-cell receptor (TCR) gene rearrangements if a clonospecific probe can be generated. However, the presence of similar sequences in IgH genes from normal B lymphocytes may decrease the specificity. For clinical purposes the crucial issues are the following. Can PCR techniques be used for confirmation of diagnosis and evaluation of extent of disease? Can PCR data obtained in remission provide information about the probability of cure or of relapse? Can techniques be developed to quantitate the PCR product and thereby increase its predictive value? These and other issues were addressed at the 4th Workshop of the Molecular Biology/BMT Study Group that took place in Bristol UK on 9-10 May 1992.

Humans↗