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Biomedical subjects

C M Morris

Publications and source records attributed to C M Morris.

144 records · Page 8Linked to original sources

Transposition of the oncogene c-ets-1 in a t(11;19)(q23;p13) cell line transient during clonal evolution of blast crisis chronic myeloid leukemia.

A patient with Ph-negative chronic myeloid leukemia showed active karyotypic evolution when he entered blast crisis. One cell line, which predominated briefly in an accelerated myeloid phase, was characterized by the t(11;19)(q23;p13). Chromosome in situ hybridization demonstrated movement of the oncogene c-ets-1 from the der (11q-) to the der (19p+). The breakpoint at 19p13 was in the vicinity of the human insulin receptor gene locus (INSR). No rearrangements of the c-ets and INSR genes were found in Southern blot analyses. Myeloid lineage was indicated by cell morphology and absence of immunoglobulin JH gene rearrangement and was supported by loss of the germ line bcr-3' gene. Chromosome rearrangements involving 11q23 and movement of c-ets-1 characterize monocytic and lymphoid leukemias and have not previously been reported in myeloid blast crisis of chronic myeloid leukemia.

Cell Transformation, Neoplastic↗

Interferon inhibition of DNA synthesis in Swiss 3T3 cells: dissociation from protein kinase C activation.

We have examined the role of protein kinase C in the anti-proliferative effects of interferon in Swiss 3T3 cells. Treatment of these cells with interferon did not stimulate the phosphorylation of an acidic Mr 80,000 cellular protein which serves as a substrate for protein kinase C. In addition, interferon did not inhibit the binding of 125I-epidermal growth factor to specific receptors or induce the expression of the proto-oncogene, c-fos in Swiss 3T3 cells. Thus, interferon does not activate protein kinase C. Moreover, interferon can still inhibit DNA synthesis in protein kinase C down-regulated 3T3 cells, indicating that the presence of this phosphotransferase is not essential for the anti-proliferative effects of interferon.

Animals↗

Complexity of an apparently simple variant Ph translocation in chronic myeloid leukemia.

A patient with chronic myeloid leukemia (CML) presented with an apparently simple Ph translocation t(19;22)(q13;q11). In-situ hybridization revealed movement of the c-abl oncogene from a cytogenetically normal chromosome 9 to the Ph. Bcr-3' and c-sis probes hybridized to distal 1p and not to the 19q+ chromosome as expected from the cytogenetic findings. We concluded that this patient had a complex translocation involving four chromosomes: t(1;9;19;22)(p36;q34;q13;q11).

Adult↗

Karyotypic evolution in a B-cell lymphoma.

A B-cell lymphoma in the lung of a 59-year-old woman showed a near-pentaploid karyotype and chromosomal changes indicating a t(8;14) in cells from a pleural aspirate. Cells from metastases to the skin and a second pleural aspirate were pseudodiploid, but showed separate further complex cytogenetic changes. Among these was a 14q+ chromosome, but the #8 chromosomes apparently were normal. It is suggested that there was a loss of the derivative 8q- chromosome from the t(8;14) followed by homozygozity of the normal #8 chromosome.

Aged↗

Ph-negative chronic myeloid leukaemia.

An analysis of five patients with Philadelphia chromosome (Ph) negative chronic myeloid leukaemia (CML) revealed that two were clinically and haematologically identical to Ph-positive CML whereas three should be reclassified as chronic myelomonocytic leukaemia (CMML). At a molecular level the first two patients showed the same juxtaposition of c-abl and bcr genes as is seen in Ph-positive CML. These genomic changes were not seen in the other three patients. Observations on these five patients suggest that the clinical course and prognosis of the rare patient who carries the Ph 'molecular defect' but lacks the Philadelphia chromosome is no different from Ph-positive CML.

Adult↗

Evidence for the repeated primary non-disjunction of chromosome 21 as a result of premature centromere division (PCD).

A clinically normal 28-year-old woman had three conceptuses with trisomy 21 and one normal child. She showed minimal cytogenetic evidence of mosaicism: 4% of her blood cells and 6% of skin fibroblasts had trisomy 21. Also, 7% of her blood cells showed aneuploidy of the X chromosome which was associated with premature centromere division (PCD,X); 6% of fibroblasts showed trisomy 18, 10% of fibroblasts showed PCD,21, and 1% PCD,18. It is unlikely that this woman is a constitutional mosaic for trisomies X, 18, and 21, all at low levels. We suggest that she has a predisposition to irregular centromere separation and that chromosomes X, 18, and 21 are most susceptible to its action.

Adult↗

An evaluation of high resolution chromosome banding of hematologic cells by methotrexate synchronization and thymidine release.

Methotrexate-thymidine synchronization increased mitotic yield and the numbers of cells with longer chromosomes when compared with direct and day culture (24 hr) techniques. The longer chromosomes overlapped more than shorter ones, but this adverse effect of cell synchronization was outweighed by the substantial gains from increased band number of metaphase cells. A critical feature of the synchronization technique that determines chromosome length is the period of cell culture following thymidine release. This will depend on cell cycle time. Variable results obtained with the synchronization technique probably occur because the cell cycle time of leukemic cells differs from that of normal hematologic cells and normal lymphocytes. It may also differ between patients and between acute and chronic forms of leukemia.

Acute Disease↗

Does multisomy of chromosome 1q confer a proliferative advantage in B-cell acute lymphoblastic leukemia?

Two patients fulfilled the clinical and hematologic criteria for B-cell acute lymphoblastic leukemia: the malignant cells had L3 morphology, bore B-cell markers, and carried the specific t(8;14) translocation. The leukemic cells of one patient were tetrasomic for 1q, and those of the other patient showed several separate cell lines with complete or partial trisomy of 1q. In the latter patient it appeared that a break close to the heterochromatin of 1q produced an unstable chromosome end which formed associations with the telomeres of at least seven other chromosomes. It is suggested that multisomy of 1q gives tumor cells a proliferative advantage and is secondary to the basic neoplastic event.

Adolescent↗

Telomeric association of chromosomes in B-cell lymphoid leukemia.

About 20% of leukemic bone marrow cells from each of two patients with B-cell lymphoid leukemias showed apparent translocations which appeared to be the result of telomeric association. In one patient, whole chromosomes were associated telomere to telomere in pairs; in the other patient, telomeres of whole chromosomes were associated with breakpoints located close to the proximal or distal ends of the heterochromatic band 1q12. Repeated base sequences, particularly (CA)n sequences, are believed to be the basis of telomere pairing, and likewise repeated base sequences of heterochromatin may explain the association of 1qh and telomeres. Telomeric association may be considered as a potential origin of new stable cytogenetic combinations that have a role in oncogene transposition and tumor etiology.

Adolescent↗

Karyotypic evolution in patients with acute myeloid leukemia.

Karyotypic evolution was found in 13 of 42 (31%) patients who were examined serially; if only those patients who were examined during successive stages of active leukemia were included, karyotypic evolution was revealed in 13 of 21 (62%). A further 6 patients showed multiple cytogenetic clones when leukemia was diagnosed. We did not find nonrandom chromosome involvement in the karyotypic changes, reported by others, notably trisomy #8. Our data for all patients who showed cytogenetic clones at some stage of their disease suggested that clones occurred with a higher incidence and arose earlier in patients with myeloblastic leukemia than in patients with myelomonocytic and monocytic leukemia. Patients showing karyotypic evolution tended to have longer than average survivals and to have had an abnormal karyotype when leukemia was diagnosed. The mode of preparation of hematologic samples, whether direct or cultured, has a bearing on karyotypic findings and could influence studies of karyotypic evolution.

Chromosome Aberrations↗

Nonrandom cytogenetic changes in New Zealand patients with acute myeloid leukemia.

Bone marrow clones with abnormal chromosomes were observed in 56% of 66 patients with forms of acute myeloid leukemia [French-American-British (FAB) M1-M6]. Acute myeloblastic leukemia (AML, M1 and M2) was the most common form, and 65% of these patients showed chromosomal abnormalities compared with 41% of patients with acute myelomonocytic leukemia (AMMoL, M4). The recognized nonrandom chromosomal abnormalities found were trisomy 8, monosomy 5 or 7, trisomy 1q, t(6;9), t(8;21), t(15;17), and abnormalities in 17q. There was also a strong involvement of chromosome No. 11: Abnormalities were found in eight patients when their leukemia was diagnosed and in a further three patients during the course of karyotypic evolution. Six of these patients had AMMoL or AMoL. Complex or multiple clones were found in 37% of AML patients at diagnosis. Our AML patients had a reduced frequency of abnormalities in chromosome No. 5 or 7 and an increased frequency of abnormalities in chromosome No. 8 compared with studies reported in other countries (p = 0.01). This difference suggests that in New Zealand AML might be caused by factors different from those operating in more industrialized centers.

Bone Marrow↗

Direct versus cultured preparation of bone marrow cells from 22 patients with acute myeloid leukemia.

The 24-h culture of bone marrow from patients with acute myeloblastic leukemia (AML) and acute promyelocytic leukemia (APL) gave more analyzable metaphase cells and improved chromosome morphology compared with direct preparations. Culture increased the proportion of cytogenetically abnormal cells, and in six bone marrows were the direct preparation failed, a result was obtained from the cultured preparation. The culture of bone marrow from patients with APL led to the detection of clones carrying the t(15;17) that were not found in direct preparations. Such sequestered clones were not found in AML and acute myelomonocytic leukemia (AMMoL). Cultured preparations were no better than direct preparations from AMMoL.

Bone Marrow↗

Cytogenetic studies of acute promyelocytic leukemia.

Translocation t(15;17) is reported in bone marrow cells from six of seven patients with active acute promyelocytic leukemia (APL). One patient who showed t(15;17) at final relapse did not show it in directly prepared or cultured cells taken from a previous relapse. Bone marrow samples from two patients showed only cells with a normal karyotype in the direct preparation, whereas more than 60% of cells cultured for 24 hr showed t(15;17). R-Banding, G-banding, and an attempt at high-resolution banding indicated the break points t(15;17)(q24;21) for one of our patients.

Adult↗

Brain iron homeostasis.

The anatomical and cellular distribution of non-haem iron, ferritin, transferrin, and the transferrin receptor have been studied in postmortem human brain and these studies, together with data on the uptake and transport of labeled iron, by the rat brain, have been used to elucidate the role of iron and other metal ions in certain neurological disorders. High levels of non-haem iron, mainly in the form of ferritin, are found in the extrapyramidal system, associated predominantly with glial cells. In contrast to non-haem iron, the density of transferrin receptors is highest in cortical and brainstem structures and appears to relate to the iron requirement of neurones for mitochondrial respiratory activity. Transferrin is synthesized within the brain by oligodendrocytes and the choroid plexus, and is present in neurones, consistent with receptor mediated uptake. The uptake of iron into the brain appears to be by a two-stage process involving initial deposition of iron in the brain capillary endothelium by serum transferrin, and subsequent transfer of iron to brain-derived transferrin and transport within the brain to sites with a high transferrin receptor density. A second, as yet unidentified mechanism, may be involved in the transfer of iron from neurones possessing transferrin receptors to sites of storage in glial cells in the extrapyramidal system. The distribution of iron and the transferrin receptor may be of relevance to iron-induced free radical formation and selective neuronal vulnerability in neurodegenerative disorders.

Animals↗

Neuroblastoma and Alzheimer's disease brain cells contain aromatase activity.

Human brain steroidogenic mechanisms, particularly aromatase, have been investigated in healthy and diseased conditions. Aromatase activity was measured in differentiated and undifferentiated neuroblastoma cell lines from mouse (TMN) and human (5H SY5Y) and in human post mortem brain samples. Neuroblastomas show much higher aromatase activity than human brain samples. Homogenates of adult human male and female cortex and frontal and temporal areas of both Alzheimer's and control patients all show considerably lower activity. The temporal area has significantly higher aromatase activity than the frontal. Aromatisation activity in differentiated neuroblastoma cells of both species is lower than in undifferentiated cells. These results are consistent with an inverse relationship between brain estrogen formation and stage of neuronal differentiation and the hypothesis that aromatase may be involved in the early stages of neuronal growth. Significant but variable activities of other androgen-metabolising enzymes, such as 5 alpha-reductase, 3 alpha/beta-hydroxysteroid dehydrogenases, and 17 beta-hydroxysteroid dehydrogenase, which generate a spectrum of regulatory molecules, are also found.

Adult↗

Genomic diversity correlates with clinical variation in Ph'-negative chronic myeloid leukaemia.

The Philadelphia chromosome (Ph') is found in the blood cells of about 90% of patients with chronic myeloid leukaemia (CML) and usually results from the reciprocal chromosome translocation t(9;22). This translocation relocates the proto-oncogene c-abl, normally found on chromosome 9q34, to within the breakpoint cluster region (bcr) on chromosome 22q11 (refs 3-8). The juxtaposition of c-abl and the 5' portion of bcr appears to be the critical genomic event in CML and results in a novel 8-kilobase (kb) fused abl/bcr transcript and a c-abl-related protein of relative molecular mass 210,000 (ref.11). About 10% of adult patients diagnosed as CML lack the Ph' chromosome; they represent a heterogeneous group of disorders which are difficult to diagnose precisely. We have examined five patients with CML whose leukaemic cells have a normal karyotype. We report here that two of the patients showed the same genomic change as occurs in Ph'-positive CML, but the change resulted from a mechanism other than chromosomal translocation. The remaining three patients showed no genomic rearrangement. This genomic diversity correlated with the clinical differences between the patients.

Adult↗