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D G Oscier

Publications and source records attributed to D G Oscier.

At least 55 records · Page 3Linked to original sources
PubMed1995

Splenic lymphoma with villous lymphocytes involves B cells with extensively mutated Ig heavy chain variable region genes.

Splenic lymphoma with villous lymphocytes (SLVL) is a recently defined subgroup of chronic B-cell lymphoproliferative diseases. The characteristic morphology of the tumor cells, together with phenotypic and cytogenetic findings, indicate that it is a distinct entity, but the nature of the cell or origin and its relationship to other low-grade lymphomas is unclear. For B-cell tumors, analysis of the variable region heavy chain (VH) genes used to encode the clonal Ig has shown marked differences between histologic categories, both in gene usage and extent of somatic mutation. An investigation of VH genes used in five typical cases of SLVL has shown somatic hypermutation from germline sequences in all cases, indicating that the cell of origin has been exposed to the hypermutation mechanism. However, no clonal heterogeneity was detectable, demonstrating that the tumor cell does not accumulate further mutations. These characteristics are similar to those found in mature postfollicular B cells, such as plasma cells. The distribution of mutations leading to replacement amino acids differed among the cases, with three of five cases showing clear evidence for antigen selection.

Aged↗
PubMed1995

Karyotypic evolution in a granulocytic sarcoma developing in a myeloproliferative disorder with a novel (3;4) translocation.

A 59-year-old man presented with a granulocytic sarcoma arising in the manubrium, and splenomegaly. The blood count showed 1.2 x 10(9)/l eosinophils and a marrow aspirate was hypercellular with eosinophilia. Cytogenetic analysis of the marrow revealed a novel t(3;4) (p13;q12) and analysis of cells aspirated from the granulocytic sarcoma showed the same abnormality and an additional trisomy 8. Intensive chemotherapy and local radiotherapy led to resolution of the chest mass but persistence of the chromosome translocation in the marrow.

Chromosomes, Human, Pair 3↗
PubMed1995

Fludarabine-related autoimmune haemolytic anaemia in patients with chronic lymphocytic leukaemia.

We have treated 52 patients with chronic lymphocytic leukaemia (CLL) with fludarabine; 12 developed severe autoimmune haemolysis. Only three had a previous history of haemolytic anaemia. Six out of eight patients retreated with fludarabine after control of their haemolysis developed an exacerbation of the haemolytic anaemia. The cause of autoimmune phenomena in CLL is not known, but our findings reinforce the view that they are caused by a disturbance in immunoregulatory T cells. Fludarabine is a known suppressor of T-cell function.

Adult↗
PubMed1994

Cytogenetic and molecular abnormalities in chronic lymphocytic leukaemia.

Genetic abnormalities are found in 50% of cases of chronic lymphocytic leukaemia (CLL) by cytogenetic analysis and in a higher percentage of patients using molecular techniques. The commonest cytogenetic abnormalities are trisomy 12 and deletions or translocations of the long arm of chromosome 13 usually involving band q14. The genetic consequences of trisomy 12 are unknown but structural abnormalities of chromosome 13q14 frequently involve hetero or homozygous loss of a region distal to the retinoblastoma gene which may be the site of a tumour suppressor gene. Trisomy 12 or loss of one copy of the retinoblastoma gene have been detected by fluorescent in situ hybridisation (FISH) in interphase cells of patients with a normal karyotype. By combining FISH with immunophenotyping, it has been found that trisomy 12 occurs in only 30 to 40% of the malignant clone, suggesting that it is a secondary event in leukaemogenesis. Trisomy 12 is strongly associated with atypical lymphocyte morphology in patients with otherwise typical CLL. Complex karyotypic abnormalities, a high percentage of abnormal metaphases and trisomy 12 but not structural abnormalities of chromosome 13 are associated with a poor prognosis at all stages of the disease. Mutations or deletions of the P53 gene are found in 10 to 15% of patients with advanced CLL and correlate with resistance to treatment and poor survival.

Chromosome Aberrations↗
PubMed1994

Establishing the incidence of myelodysplastic syndrome.

We studied the incidence of myelodysplastic syndrome (MDS) in a population served by one district general hospital over a 10-year period (1981-90). Cases were sought through investigation of individuals presenting with suggestive peripheral blood findings. 279 new cases were diagnosed in a population rising from 203,000 to 226,000 over the study period. The observed incidence rate did not change over the study period. The crude incidence rate was 12.6/100,000/year. Age-specific incidence rates per 100,000 per year were 0.5 for age < 50, 5.3 for age 50-59, 15 for age 60-69, 49 for age 70-79, and 89 for age 80+. A cohort study of one large general practice revealed several previously unknown and asymptomatic cases, indicating that the observed figures for the population overall may still underestimate the real incidence. We conclude that MDS is more common than reported in previous studies and that incidence continues to rise into very old age. Difficulties in case ascertainment hamper reliable estimates of true incidence.

Adult↗
PubMed1994

Assessment of the role of clonogenic B lymphocytes in the pathogenesis of multiple myeloma.

The identifiable neoplastic cell in multiple myeloma is the plasma cell, which usually synthesizes and secretes a monoclonal immunoglobulin. However, there exists the possibility that the neoplastic event has occurred in a less mature clonally-related cell, such as a B lymphocyte, prior to Ig class switching. Since the presence of such a clonogenic cell could influence design of therapy, particularly with monoclonal antibodies, we have used the analysis of tumour-related VH genes to approach this question. Cloning and sequencing of PCR products from VH genes of tumour cells obtained from 4/4 patients with myeloma revealed significant mutation of the genes as compared to germ line sequences. In all cases the mutations were scattered throughout the variable region, with a pattern which did not indicate a role for antigen in selection. Importantly for therapy, multiple VH sequences from all patients were completely homogeneous, with no intraclonal variation. These findings indicate that, although IgM-positive clonogenic cells may exist, it is unlikely that they are involved in continuous maintenance of the malignant isotype-switched cell population. One possibility is that the B-cell progenitor population has to undergo further chromosomal changes to generate the malignant cell, and that this occurs at a more mature stage; in this case, antibody therapy should be aimed primarily at the more differentiated cells.

Amino Acid Sequence↗
PubMed1994

Frequent homozygous deletions of the D13S25 locus in chromosome region 13q14 defines the location of a gene critical in leukaemogenesis in chronic B-cell lymphocytic leukaemia.

Cytogenetic studies of B-cell chronic lymphocytic leukaemia show structural abnormalities involving the 13q14 chromosome region as the only karyotypic change in a significant proportion of tumours. This observation suggests the location of a gene important in leukaemogenesis. A series of 68 BCLL tumours have been analysed for allele loss using a series of probes from 13q14. Using intragenic polymorphic markers from the retinoblastoma predisposition gene LOH was observed in 25% of tumours including 3/6 showing cytogenetically obvious deletions of the 13q14 region and 3/6 showing translocations involving 13q14. However, three deletions with proximal breakpoints in 13q14 did not show allele loss, demonstrating that the breakpoint lay distal to RB1. Using the D13S25 locus, which lies 1.6 cM distal to RB1, allele loss was seen in 90% of tumours with structural rearrangements of 13q14 and 75% of tumours with an apparently normal karyotype. 50% of these tumours showed homozygous loss of D13S25, suggesting that a 'tumour suppressor gene' lies in this region. The more distal D13S31 locus, 1 cM distal to D13S25, was infrequently involved in allele loss demonstrating that the minimum region of overlap for homozygous deletions is approximately 1 Mbp around the D13S25 locus.

Alleles↗
PubMed1993

Comparison of cytogenetic and restriction fragment length polymorphism analyses for the detection of loss of chromosome material in clonal hemopoietic disorders.

Loss of chromosome material, as manifested by monosomy or partial deletion, is commonly found in neoplastic cells. We have undertaken a systematic comparison of standard cytogenetic analysis and molecular analysis for the detection of such loss, using as a model loss of chromosome 7 in 72 patients with a clonal myeloid malignancy. A large number of probes was used to screen three regions of chromosome 7 for loss by restriction fragment length polymorphism (RFLP) analysis. There were nine cases in which loss of chromosome 7 was detected by both techniques, but seven in which loss was detected by only one of the methods, demonstrating the complementary nature of these two techniques.

Aged↗
PubMed1993

Cytogenetic studies in splenic lymphoma with villous lymphocytes.

We report the cytogenetic findings on 31 cases of splenic lymphoma with villous lymphocytes (SLVL). TPA stimulated cells from peripheral blood (28 cases), spleen (two cases) and lymph node (one case) with SLVL have been analysed. A clonal chromosome abnormality was found in 27/31 patients (87%); this was identified as a simple abnormality in 12 cases and a complex one in 15. Four recurring abnormalities were seen: t(11;14)(q13;q32) in five patients, deletions or translocations involving 7q in seven patients, iso 17q in four patients and translocations involving 2p11 in four patients. The high frequency of clonal chromosome abnormalities in SLVL contrasts with the usually benign clinical course of this disease. Abnormalities found frequently in patients with chronic lymphocytic leukaemia (CLL) such as trisomy 12 and deletions or translocations involving 13q14 were each seen in only one patient. No case had the t(14;18) characteristic of follicular lymphoma. Our findings demonstrate the high frequency of clonal and often complex chromosome abnormalities in SLVL. Although a unique chromosome rearrangement has not been identified, a pattern of four recurrent abnormalities has emerged. Our results suggest that SLVL is distinct on cytogenetic grounds from B-CLL and follicular lymphoma but shows similarity with mantle cell lymphoma, lymphoplasmacytic lymphoma and B-PLL.

Adult↗
PubMed1993

Use of a retinoblastoma gene probe to investigate clonality in Richter's syndrome.

A 69-year-old woman presented with Rai stage 0 chronic lymphocytic leukemia. Ten years later she developed a diffuse centroblastic lymphoma involving the stomach. The surface membrane phenotype of the CLL cells was MD lambda while that of the large cell lymphoma (LCL) cells was MD kappa. The two populations had different heavy and kappa light chain rearrangements. Cytogenetic analysis of the CLL cells showed a deletion involving chromosome 13, band q14, but was unsuccessful in the LCL cells. However, use of a probe (p68 RS2.0) which recognizes a variable number tandem repeat sequence in the retinoblastoma gene, localized to chromosome 13q14, showed two alleles in the LCL cells but only one in the CLL cells. These data suggest that in this case of Richter's syndrome the CLL cells and the LCL cells are clonally distinct.

Aged↗
PubMed1992

"Stem cell" origin of the hematopoietic defect in dyskeratosis congenita.

We have used the long-term bone marrow culture (LTBMC) system to analyze hematopoiesis in three patients with dyskeratosis congenita (DC), two of whom had aplastic anemia, and the third had a normal blood count (apart from mild macrocytosis) and normal BM cellularity. Hematopoiesis was severely defective in all three patients, as measured by a low incidence of colony-forming cells and a low level of hematopoiesis in LTBMC. The function of the marrow stroma was normal in its ability to support the growth of hematopoietic progenitors from normal marrows seeded onto them in all three cases, but the generation of hematopoietic progenitors from patients marrow cells inoculated onto normal stromas was reduced, thus suggesting the defect to be of stem cell origin. The parents and unaffected brother of one of the families have also been studied in LTBMC and all showed normal hematopoietic and stromal cell function. From this study we speculate that there are some similarities between DC and the defect in the W/Wv mouse.

Adolescent↗
PubMed1991

Loss of both CSF1R (FMS) alleles in patients with myelodysplasia and a chromosome 5 deletion.

A high proportion of patients with myelodysplasia show characteristic karyotypic abnormalities in bone marrow cells. The most distinctive of the myelodysplastic syndromes is the 5q- syndrome characterized by refractory anemia, poorly lobulated megakaryocytes, and an interstitial deletion of the long arm of chromosome 5 (5q deletion) as the sole karyotypic abnormality. Recently, several genes encoding hemopoietic growth factors and receptors, comprising the interleukins 3, 4, and 5, macrophage colony-stimulating factor, granulocyte/macrophage-colony-stimulating factor, and the receptor for macrophage-colony-stimulating factor [the CSF1R (formerly FMS) gene product], have been localized to the long arm of chromosome 5, and there has been much speculation that deletion of one or more of these genes may be critical to the pathogenesis of the associated myeloid disorders. One candidate gene is CSF1R, which is required for normal proliferation and differentiation of hemopoietic cells of the myeloid lineage. We have carried out a molecular examination of the CSF1R, both on the 5q- chromosome and on the apparently normal homologous chromosome 5, in 10 patients with myelodysplasia and a 5q deletion. We have found, using restriction fragment length polymorphism analysis and gene dosage experiments, that all 10 patients showed deletion of CSF1R; 6 of 10 were hemizygous and 4 of 10 homozygous for CSF1R loss. The homozygous CSF1R loss has been confirmed in 2 patients by an in situ hybridization technique comparing the signal in affected cells to that in control sex-mismatched cells on the same slides. In those patients considered to have homozygous CSF1R loss by DNA experiments the gene was deleted from the 5q chromosome in all cells and from the apparently normal chromosome 5 in a subset of cells. This loss of one CSF1R allele, together with loss in some cells of the remaining allele on the homologous chromosome 5, in patients with myelodysplasia indicates that this is a region of critical gene loss on 5q. The loss of the hemopoietic growth factor receptor gene CSF1R may be important in the pathogenesis of human myeloid leukemia.

Adult↗
PubMed1991

Translocation 1;7 in hematologic disorders--a report of three further cases. Absence of amplification of the gene for the epidermal growth factor receptor.

We report three new cases with a hematologic disorder and the unbalanced translocation der(1)t(1;7)(p11;p11). It has been speculated that the gene for the epidermal growth factor receptor, localized to the short arm of chromosome 7, might be amplified in cases with this translocation. We have demonstrated that there is no amplification of this gene in these three cases.

Aged↗
PubMed1991

Clonality of cell populations in refractory anaemia using combined approach of gene loss and X-linked restriction fragment length polymorphism-methylation analyses.

We have used X-linked restriction fragment length polymorphism (RFLP)-methylation and gene deletion analyses to investigate the nature of the progenitor cell of origin in the myelodysplastic syndromes (MDS). Gene deletion studies were performed on the granulocyte and T-lymphocyte fractions of six women with refractory anaemia (RA) and either a partial deletion of the long arm of chromosome 5 (5q-) or monosomy 7. All six showed gene loss in the granulocyte but not the T-lymphocyte fractions, indicating monoclonality of the granulocytes but not the T-lymphocytes. In order to further investigate this finding, we subsequently performed X-RFLP-methylation studies using the probe M27 beta, and also a probe for the phosphoglycerate kinase (PGK) gene. These studies have confirmed the monoclonality of the granulocytes and the polyclonality of the T-lymphocytes in these cases. Our findings suggest that in this group of patients with MDS the T-lymphocytes were not involved in the disorder, and furthermore, in the one case where B-lymphocytes were also available, that the progenitor cell of origin was restricted to the myeloid lineage.

Anemia, Refractory↗
PubMed1991

Red cell aplasia in myelodysplastic syndrome.

Six cases of red cell aplasia occurring in patients with myelodysplastic syndromes (MDS) showed a diversity of clinical course and prognosis. In some patients red cell aplasia may have represented an evolution of MDS while in others autoimmune destruction of erythoblasts may have been the mechanism. A proliferative phase is seen in many of these patients, the clinical importance of which is uncertain.

Aged↗