Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The first consistent karyotypic abnormality found to be associated with neoplastic disease was the Philadelphia (Ph) chromosome (Nowell & Hungerford, 1960). Furthermore, the best-studied example of translocation-mediated gene activation occurs in leukaemia patients bearing this abnormality (reviewed by Kurzrock et al, 1988). In these individuals, the Ph translocation (t(9;22)(q34;q11)) results in transposition of the ABL proto-oncogene from chromosome 9q34 to 22q11, where it is fused with part of the BCR gene. It is now known that as a result of the Ph translocation, p160BCR and p145ABL (the normal BCR and ABL gene products) are replaced by p210BCR-ABL. This aberrant protein constitutes the molecular fingerprint of CML. The enhanced tyrosine phosphokinase enzymatic activity (a property possessed by some growth factor receptors and transformation-inducing oncogenes) of p210BCR-ABL implicates a direct role for this molecule in the pathogenesis of CML. Because the Ph translocation is present in the early chronic phase, the union of the BCR and ABL genes is probably involved in the initiation of the leukaemic process. The secondary molecular forces driving progression of CML to blast crisis are however unknown, and may differ from patient to patient. Approximately 10% of CML patients lack a Ph chromosome. One-half of these individuals have bcr rearrangement and express p210BCR-ABL. Ph+ and Ph- bcr+ (p210+) CML are identical and should be treated the same. Molecular follow-up of diploid bcr+ CML patients is essential for detection of persistent malignancy after therapy. The presence of a specific marker--the BCR-ABL message--permits the development of new diagnostic approaches for CML. For instance, detection of a BCR-ABL message with the use of the highly sensitive polymerase chain reaction, a technique capable of detecting up to one leukaemia cell amongst one million normal cells, yields important information about minimal residual disease. Finally, the use of therapy directed against the BCR-ABL product may be a worthwhile strategy which deserves investigation, and may prompt a new era of tumour-specific treatment.
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PMID:The molecular pathology of chronic myelogenous leukaemia. 193 6

The gene (E2A) for enhancer binding transcription factors E12 and E47 maps to the t(1;19) chromosomal translocation breakpoint in pre-B cell leukemias. Altered E2A transcripts lacking sequences coding for the helix-loop-helix DNA binding motif were detected in several t(1;19)-carrying cell lines. Fusion cDNAs that crossed the t(1;19) breakpoint were cloned and shown to code for an 85 kd protein consisting of the amino-terminal two-thirds of E2A fused to a chromosome 1-derived protein. The fusion protein has the features of a chimeric transcription factor in which the DNA binding domain of E2A is replaced by the putative DNA binding domain of a homeoprotein from chromosome 1 for which the name Prl (pre-B cell leukemia) is proposed. Identical E2A-prl mRNA junctions were detected by PCR in three t(1;19)-carrying cell lines, indicating that the fusion transcripts and predicted chimeric protein are a consistent feature of this translocation.
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PMID:Chromosomal translocation t(1;19) results in synthesis of a homeobox fusion mRNA that codes for a potential chimeric transcription factor. 196 82

The effects of a ligand regulated neu tyrosine kinase were examined in NIH 3T3 cells. A chimeric construct encoding the human EGF receptor extracellular domain fused to the tyrosine kinase domain of the rat neu cDNA was expressed under the transcriptional control of the Moloney murine leukemia virus LTR promoter. This resulted in higher levels of expression of the chimeric receptor than were previously obtained from the SV40 virus early promoter in the same cells. The chimeric receptor showed strict ligand-dependent tyrosine kinase and signal transducing activities for the induction of growth-regulated biochemical activities and DNA synthesis in resting cells. The ligand-activated cells became morphologically transformed and grew in agar in the presence of EGF and TGF beta as efficiently as did the ligand-independent neu oncogene-transformed cells. Our results establish similarities between the signal pathways of the EGF receptor and the neu tyrosine kinase.
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PMID:Regulation by EGF is maintained in an overexpressed chimeric EGFR/neu receptor tyrosine kinase. 196 20

Usefulness of DNA analysis in diagnosis of hematopoietic malignancy was discussed. Examination on the presence of rearrangement in immunoglobulin (Ig) and T cell receptor (TCR) was the first DNA analysis used for clinical diagnosis of lymphoid malignancy to determine the cell-lineage and clonality of proliferating lymphoid cells. One point mutation in ras oncogene has also been used to detect residual leukemic cells as well as diagnosis of the early relapse of leukemia, although not all leukemic cells have this mutation. Presence of BCR-abl fused gene is a genetic marker for Ph1 chromosome. Analysis of BCR-abl gene has made it possible to diagnose the Ph1 ALL and masked Ph1 CML. Development of PCR technique markedly increased the possibility for the use of DNA analysis in clinical medicine. In addition to Ph1 chromosome, various chromosomal abnormalities resulted in a reciprocal translocation between Ig or TCR gene and other genes in various lymphoid malignancies, such as Burkitt lymphoma and follicular lymphoma. These translocations can be analyzed by Southern hybridization and used for clinical diagnosis.
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PMID:[DNA diagnosis of human cancers: lymphoid malignancies and leukemia]. 198

We have investigated the regulation of DNA synthesis in the heterokaryons of HL60 human myelomonocytic leukemia cells and NIH3T3 mouse fibroblasts to examine if the differentiated leukemia cells contained a replication inhibiting activity. Cell fusions were performed either by exposing a suspension of mixed cells to an electric pulse or by the polyethylene glycol method. To identify the origin of the nuclei in a heterokaryon, one set of partner cells was prelabeled with [3H]thymidine before fusion. DNA synthetic activity after fusion was then revealed immunohistochemically by bromodeoxyuridine incorporation. DNA synthesis in the nuclei of 3T3 was inhibited in the heterokaryons of 3T3 and in either one of the two differentiated forms of HL60, i.e., the macrophage-like or the granulocyte-like. The result supports that a negative regulator of DNA synthesis exists in the differentiated HL60. Surprisingly, we have also found that DNA synthesis was inhibited in the nuclei of both 3T3 and nondifferentiated, proliferating HL60 when these two cells were fused. When unfused, proliferating cells were eliminated with cytosine arabinoside; these nonreplicating heterokaryons survived for at least 5 days, and 15% of them showed alpha-naphthylacetate esterase activity, a trait of the macrophage differentiation. The blockage of DNA synthesis in both partner nuclei was also observed in the heterokaryons of NIH3T3 cells and nondifferentiated human promonocytic leukemia cells U937, and in nondifferentiated HL60 and human diploid fibroblasts WI38. However, this effect was not found in the heterokaryons of NIH3T3 cells and human B lymphoma WI-729-HF2 cells. This is the first demonstration of the inhibition of DNA synthesis upon fusion of two proliferating cells.
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PMID:Fusion of fibroblasts with differentiated and nondifferentiated leukemia cells resulting in blockage of DNA synthesis. 201 30

More than 95% of patients with chronic myelogenous leukemia (CML) contain an abnormal chromosome termed the Philadelphia chromosome (Ph1). Ph1 and the resulting BCR-ABL fused genes are markers for this type of leukemia. The product of the fused BCR-ABL genes is a protein of about 2000 amino acids termed P210 BCR-ABL. Although the BCR-ABL protein can be routinely detected in blood cells from blast crisis CML patients by assaying for its activated tyrosine kinase activity, detection of P210 BCR-ABL in early stage CML patients (chronic phase) has not yet been possible (S. A. Maxwell et al., Cancer Res., 47: 1731, 1987). A procedure involving Western blotting with an anti-ABL monoclonal antibody was developed that allows detection of P210 BCR-ABL and P145 ABL in cells from chronic phase and blast crisis CML patients, but as expected only P145 ABL was found in normal white blood cells. Most chronic phase patients also contained one to two ABL proteins with a molecular weight of about 190,000. Interestingly, the ratio of BCR-ABL to ABL proteins increased in four blast crisis patients compared to 18 chronic phase patients. Also, one chronic phase patient analyzed on three separate occasions lacked P210 BCR-ABL and exhibited only the Mr 190,000 form. This assay should also be useful in other leukemias that express altered forms of the ABL protein.
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PMID:Detection of BCR-ABL proteins in blood cells of benign phase chronic myelogenous leukemia patients. 203 43

The Ph chromosome was the first specific karyotype abnormality associated with a particular neoplastic disease in humans. For many years it was suspected that chromosome abnormalities might cause cancer by alteration of specific genes or their expression. Significant recent developments in our understanding of the molecular consequences of the Ph translocation strengthen that assumption. The Ph translocation generates a hybrid gene consisting of 5' regulatory, promotor, and exon sequences of the bcr gene on chromosome 22 fused to 3' exons and polyadenylation/termination sequences of the ABL proto-oncogene from chromosome 9. It is well established that fusion of bcr and abl genes plays a crucial role in the pathogenesis of CML and ALL. Molecular methods can therefore be used as diagnostic tools to detect the Ph chromosome. Presently, the model of oncogenesis provided by our knowledge of how the abl proto-oncogene becomes activated as a result of the Ph translocation is one of the clearest models of oncogene activation. Despite the progress made, many areas remain to be explored. One important question is, how the hybrid protein is involved in leukemia. Research aimed at investigating the normal function of abl and bcr may be important in efforts to understand their abnormal functioning in leukemia and to increase our understanding of the disease.
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PMID:Molecular insights into the Philadelphia translocation. 205 Jun

The highly leukemogenic avian retrovirus E26 expresses the two transcriptional activator-type oncogenes v-myb and v-ets as a nuclear fusion protein. Previous studies have shown that both oncogenes cooperate in the transformation of erythroid cells in vitro and that the phenotypes of transformed cells differ, depending on whether the oncogenes are coexpressed as separate proteins or as a fusion protein. Here we show that virus constructs encoding either v-Myb or v-Ets as their only oncoprotein are nonleukemogenic and that constructs coexpressing nonfused v-Myb and v-Ets proteins appear to be weakly leukemogenic. Surprisingly, leukemic animals injected with the latter contain highly leukemogenic variant viruses that exhibit internal deletions in their genome, resulting in the synthesis of novel Myb-Ets fusion proteins. These results show that v-Myb and v-Ets must be fused to cause leukemia and establish a new mechanism of oncogene activation and cooperation.
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PMID:Fusion of the nuclear oncoproteins v-Myb and v-Ets is required for the leukemogenicity of E26 virus. 207 Apr 21

The irradiation-fusion technique offers a means to isolate intact subchromosomal fragments of one mammalian species in the genetic background of another. Irradiation-reduced somatic cell hybrids can be used to construct detailed genetic and physical maps of individual chromosome bands and to systematically clone genes responsible for hereditary diseases on the basis of their chromosomal position. To assess this strategy, we constructed a panel of hybrids that selectively retain the portion of human chromosome band 11p13 that includes genes responsible for Wilms tumor, aniridia, genitourinary anomalies, and mental retardation (constituting the WAGR syndrome). A hamster-human hybrid containing the short arm of chromosome 11 as its only human DNA (J1-11) was gamma-irradiated and fused to a Chinese hamster cell line (CHO-K1). We selected secondary hybrid clones that express MIC1 but not MER2, cell-surface antigens encoded by bands 11p13 and 11p15, respectively. These clones were characterized cytogenetically by in situ hybridization with human repetitive DNA and were tested for their retention of 56 DNA, isozyme, and antigen markers whose order on chromosome 11p is known. These cell lines appear to carry single, coherent segments of 11p spanning MIC1, which range in size from 3000 kb to more than 50,000 kb and which are generally stable in the absence of selection. In addition to the selected region of 11p13, two cell lines carry extra fragments of the human centromere and two harbor small, unstable segments of 11p15. As a first step to determine the size and molecular organization of the WAGR gene complex, we analyzed a subset of reduced hybrids by pulsed-field gel electrophoresis. A small group of NotI restriction fragments comprising the WAGR complex was detected in Southern blots with a cloned Alu repetitive probe. One of the cell lines (GH3A) was found to carry a stable approximately 3000-kb segment of 11p13 as its only human DNA. The segment encompasses MIC1, a recurrent translocation breakpoint in acute T-cell leukemia (TCL2), and most or all of the WAGR gene complex, but does not include the close flanking markers D11S16 and delta J. This hybrid forms an ideal source of molecular clones for the developmentally fascinating genes underlying the WAGR syndrome.
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PMID:A panel of irradiation-reduced hybrids selectively retaining human chromosome 11p13: their structure and use to purify the WAGR gene complex. 215 97

FeLV-FAIDS, an immunodeficiency-inducing isolate of feline leukemia virus, is composed of a pathogenic but replication-defective genome (molecular clone 61C) and a replication-competent but non-immunodeficiency-inducing variant genome (molecular clone 61E). The chimeric virus EECC, composed of the 5' gag-pol of 61E fused to the env-3' LTR of 61C, also induces immunodeficiency. The 61C (or EECC) gp80 can be distinguished from that of 61E on the basis of antigenic recognition, size, and rate of posttranslational processing. We found that the nascent precursor polypeptides of the two viruses were the same size; however, the 61E gp80 rapidly shifted to a smaller size and was subsequently cleaved to gp70, whereas EECC gp80 maintained its nascent size and was cleaved to gp70 only after a prolonged time. Endo-beta-N-acetyl glucosaminidase H and N-glycanase digestions of newly formed glycoproteins resulted in a similar banding pattern for both viruses, indicating that both contained the same number of oligosaccharide side chains and that all of these were high mannose sugars. The metabolic inhibitors of glycosylation, castanospermine or N-methyldeoxynojirimycin, prevented both the rapid trimming of 61E gp80 and its cleavage to gp70. Treatment with mannosidase inhibitors, however, did not affect 61E gp80 processing or size, suggesting that retention of glucose residues on EECC was responsible for these distinguishing properties of the glycoprotein. The pathological consequence of aberrant viral glycoprotein processing was evaluated in feline 3201 T lymphocytes, which are infectable by both 61E and EECC but are killed only by EECC. As in fibroblasts, the EECC glycoprotein produced in lymphocytes was larger, antigenically distinct, and processed more slowly than was the glycoprotein of 61E. Castanospermine treatment of 61E-infected 3201 T cells, however, not only abrogated the antigenic differences between the 61E and EECC glycoproteins but also resulted in a cytopathic effect. Our results suggest that (i) intracellular accumulation of EECC envelope glycoprotein may occur consequent to retention of glucose residues on carbohydrate side chains and (ii) a strong correlation exists between delayed glycoprotein processing and cytopathicity in FeLV-FAIDS-infected T lymphocytes.
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PMID:Characterization and significance of delayed processing of the feline leukemia virus FeLV-FAIDS envelope glycoprotein. 216 20


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