Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0598766 (leukemogenesis)
 4,065 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Two forms of activated BCR/ABL proteins, P210 and P185, that differ in BCR-derived sequences, are associated with Philadelphia chromosome-positive leukemias. One of these diseases is chronic myelogenous leukemia, an indolent disease arising in hematopoietic stem cells that is almost always associated with the P210 form of BCR/ABL. Acute lymphocytic leukemia, a more aggressive malignancy, can be associated with both forms of BCR/ABL. While it is virtually certain that BCR/ABL plays a central role in both of these diseases, the features that determine the association of a particular form with a given disease have not been elucidated. We have used the bone marrow reconstitution leukemogenesis model to test the hypothesis that BCR sequences influence the ability of activated ABL to transform different types of hematopoietic cells. Our studies reveal that both P185 and P210 induce a similar spectrum of hematological diseases, including granulocytic, myelomonocytic, and lymphocytic leukemias. Despite the similarity of the disease patterns, animals given P185-infected marrow developed a more aggressive disease after a shorter latent period than those given P210-infected marrow. These data demonstrate that the structure of the BCR/ABL oncoprotein does not affect the type of disease induced by each form of the oncogene but does control the potency of the oncogenic signal.
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PMID:Differences in oncogenic potency but not target cell specificity distinguish the two forms of the BCR/ABL oncogene. 187 48

The Philadelphia (Ph) translocation t(9;22)(q34;q11) occurs frequently in chronic myeloid leukemia (CML) but is less common in acute lymphoblastic leukemia (ALL) and rare in acute myeloid leukemia (AML). In most cases of CML and some cases of Ph+ ALL the protooncogene ABL from 9q34 is translocated to the breakpoint cluster region (bcr) of the BCR gene at 22q11 to form a chimeric gene encoding a novel 210-kd protein (P210 BCR-ABL) with enhanced tyrosine kinase activity. In other patients with Ph+ ALL and Ph+ AML, the breakpoint probably occurs in the first intron of the BCR gene; this results in a smaller chimeric gene which encodes a P190 BCR-ABL. We studied a patient with AML (FAB M6) arising de novo who had a "masked" Ph chromosome in association with extensive karyotypic changes. The leukemic cells initially showed rearrangement of the bcr, presence of a hybrid mRNA, and expression of the P210 BCR-ABL. These changes were absent in remission. These results support the concept that the BCR-ABL chimeric gene plays a crucial role in leukemogenesis but suggest that factors other than the position of the breakpoint in the BCR gene determine the lineage of the target cell for malignant transformation.
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PMID:Rearrangement of the breakpoint cluster region and expression of P210 BCR-ABL in a "masked" Philadelphia chromosome-positive acute myeloid leukemia. 317 49

Philadelphia (Ph)-positive leukemias invariably contain a chromosomal translocation fusing BCR to ABL. The BCR-ABL protein is responsible for leukemogenesis. Here we show that exposure of bcr-null mutant mice to gram-negative endotoxin led to severe septic shock and increased tissue injury by neutrophils. Neutrophils of bcr (-/-) mice showed a pronounced increase in reactive oxygen metabolite production upon activation and were more sensitive to priming stimuli. Activated (-/-) neutrophils displayed a 3-fold increased p21rac2 membrane translocation compared with (+/+) neutrophils. These results connect Bcr in vivo with the regulation of Rac-mediated superoxide production by the NADPH-oxidase system of leukocytes and suggest a link between Bcr function and the cell type affected in Ph-positive leukemia.
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PMID:Increased neutrophil respiratory burst in bcr-null mutants. 788 65

The translocation (6;9) in acute nonlymphocytic leukemia results in the formation of a dek-can fusion gene. In a case of acute undifferentiated leukemia, the oncogene can is fused to a different gene, named set, instead of dek and is assumed to be activated. Transcripts of set encode a putative SET protein with a predicted molecular mass of 32 kDa. We identified SET as a 39-kDa protein by immunoprecipitation with rabbit antiserum against each of three synthetic peptides predicted from the open reading frame of the set gene. We confirmed this identification of SET by protein sequencing. We also observed that SET is expressed ubiquitously in various human cell lines. SET is phosphorylated on serine residue(s) in cultured cells and is localized predominantly in nuclei. Although the function(s) of SET and SET-CAN is not known, we propose that SET plays a key role in the mechanism of leukemogenesis in acute undifferentiated leukemia, perhaps by activating CAN in nuclei and stimulating the transformation potential of SET-CAN. This proposed role would therefore be similar to the roles observed for BCR and DEK of the chimeric oncoproteins BCR-ABL and DEK-CAN in acute myeloid leukemia and acute nonlymphocytic leukemia, respectively.
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PMID:Identification and characterization of SET, a nuclear phosphoprotein encoded by the translocation break point in acute undifferentiated leukemia. 829 83

The Philadelphia chromosome consists of a reciprocal translocation between the ABL oncogene at chromosome 9q34 and the BCR gene at chromosome 22q11, resulting in the expression of chimeric BCR-ABL mRNAs specific to chronic myelogenous leukemia (CML). Presence of the fusion gene can be detected with high specificity and sensitivity by means of reverse transcription and polymerase chain reaction. Using this assay, it was possible to detect BCR-ABL fusion genes induced among HL60 cells after 100 Gy of X-irradiation in vitro. In total, five fusion gene transcripts were obtained among 10(8) cells examined. These fusion genes contained not only CML-specific BCR-ABL rearrangements, but also other forms of BCR-ABL fusions. These latter genes had junctions of BCR exon 4/ABL exon 2 intervened by a segment of DNA of unknown origin, BCR exon 5/ABL exon 2, and BCR exon 4/ABL exon 2. The results appear to be direct evidence for the induction of the BCR-ABL fusion gene by X-irradiation. In terms of leukemogenesis, it appears that only those cells bearing certain CML-related BCR-ABL fusion genes are positively selected by virtue of a growth advantage in vivo.
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PMID:Induction of BCR-ABL fusion genes by in vitro X-irradiation. 846 27

Recent advances in molecular cytogenetics of leukemia is reported with special reference to the pathogenesis, diagnosis, prognosis, and potential gene therapy. Regarding leukemogenesis, we found that neocarzinostatin induced a variety of deletions and reciprocal translocations. Among these random chromosome abnormalities, two reciprocal translocations which were specific for certain leukemias could be observed; t(11;14)(q13;q32) and t(7;11)(p15p13). This fact suggests that a translocation carrying oncogene rearrangement may be of potential relevance to the leukemogenesis. The success in making a subgroup (FAB classification) identified a number of subtype-specific translocations in leukemias. It has been suggested that an initiation or progression-associated event is mediated through a gross chromosomal change. The molecular characterization of chromosomal rearrangement leads to the identification of genes involved in leukemia. Our recent works in molecular cytogenetics of chronic myelogenous leukemia (CML), acute lymphoblastic leukemia (ALL), FAB-M3 and -M4 were shown in this article. Since rearrangement of relevant genes were cloned, PCR made it feasible to detect minimal residual disease at 10(-6) level after intensive treatment or bone marrow transplantation for CML, Ph-positive ALL, M3 and approximately half of childhood leukemia. Recently developed fluorescent in situ hybridization (FISH) using specific probes can visualize certain chromosomes or chromosomal segments. Ph translocation, for instance, is now demonstrated as three spot-signals in interphase nuclei using YAC (yeast artificial chromosome)-BCR clone. Lastly, the use of antisense oligonucleotides for the BCR-ABL junctions should result in the inhibition of growth of CML clone. The strategy using antisense molecules may be very powerful tool in the gene-targeting therapy for human neoplasms.
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PMID:[Recent advances in molecular cytogenetics of leukemia]. 847 75

Recently, clinical application of gene technology in oncology and hematology has been markedly advanced. Pathogenesis of leukemic transformation has been thought that it was resulted from cumulation of activation or mutation in oncogenes or onco-suppressor genes. As a matter of fact, many specific chromosomal abnormalities in leukemias have been thought to be due to production of chimeric fusion gene by translocation and activation in some kinds of oncogenes under specific regulatory genes after translocation. In addition to those, inactivation of onco-suppressor genes, such as RB gene or p53 gene, may be also related to leukemogenesis in some leukemias. Laboratory examinations using molecular technology are being necessary for clinical diagnosis and treatment in many hematological disorders. The examinations detecting rearrangement of major BCR or minor BCR in Ph1 positive leukemias, TCR in T cell malignancy, immunoglobulin in B cell malignancy, PML-RAR alpha fusion gene in APL have become routine for diagnosis of some leukemias. Moreover, these examinations are useful for judgement of treatment effects and evaluation of minimal residual diseases. In this paper, we also discuss the usefulness and importance of these technology especially in stem cell transplantation and cytokine therapy, and the future possibility in this technology for gene therapy.
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PMID:[Clinical application of gene technology for diagnosis and treatment of leukemia]. 902 44

BCR-ABL(p190) oncogene is the result of a reciprocal translocation between chromosomes 9 and 22 and is associated with B-cell acute lymphoblastic leukemia (B-ALL) in humans. Current models expressing the BCR-ABL(p190) chimeric gene fail to consistently reproduce the phenotype with which the fusion gene is associated in human pathology, mainly due to the difficulty of being expressed in the appropriate cell type in vivo. We have used here homologous recombination in ES cells to create an in-frame fusion of BCR-ABL(p190) that mimics the consequences of the human chromosomal translocation by fusion of BCR-ABL coding sequences into the bcr endogenous gene. The chimeric mice generated with the mutant embryonic stem cells systematically develop B-ALL. Using these chimeric mice, we further show that BCR-ABL oncogene does not require the endogenous bcr product in leukemogenesis. Our results show that BCR-ABL(p190) chimeric mice are a new model to study the biology of the BCR-ABL oncogene and indicate the efficacy of this strategy for studying the role of specific chromosome abnormalities in tumor development.
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PMID:A BCR-ABL(p190) fusion gene made by homologous recombination causes B-cell acute lymphoblastic leukemias in chimeric mice with independence of the endogenous bcr product. 931 Apr 67

There is strong clinical and epidemiological evidence that ionizing radiation can cause leukemia by inducing DNA damage. This crucial initiation event is believed to be the result of random DNA breakage and misrepair, whereas the subsequent steps, promotion and progression, must rely on mechanisms of selective pressure to provide the expanding leukemic population with its proliferative/renewal advantage. To investigate the susceptibility of human cells to external agents at the genetic recombination stage of leukemogenesis, we subjected two hematopoietic cell lines, KG1 and HL60, to high doses of gamma-irradiation. The irradiation induced the formation of fusion genes characteristic of leukemia in both cell lines, but at a much higher frequency in KG1 than in HL60. In KG1 cells, the AML1-ETO hybrid gene [associated with the t(8;21) translocation of acute myeloid leukemia] occurred significantly more often than the BCR-ABL [associated with t(9;22) chronic myeloid leukemia] or the DEK-CAN [associated with t(6;9) acute myeloid leukemia] fusion genes. These findings support the notion that ionizing radiation can directly generate leukemia-specific fusion genes but emphasize the differing susceptibility of different cell populations and the differing frequency with which the various fusion genes are formed. The selectivity observed at the primary level of gene fusion formation may explain at least in part the differential risk for development of some but not other forms of leukemia after high-dose radiation exposure.
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PMID:Selective induction of leukemia-associated fusion genes by high-dose ionizing radiation. 945 83

The Philadelphia (Ph) chromosome, the main product of the (9;22)(q34;q11) translocation, is the cytogenetic hallmark of chronic myeloid leukemia (CML), a clonal myeloproliferative disorder of the hematopoietic stem cell; the Ph chromosome is also found in a sizeable portion of acute lymphoblastic leukemia (ALL) patients and in a small number of acute myeloid leukemia (AML) cases. At the molecular level, the t(9;22) leads to the fusion of the BCR gene (on chromosome 22) to the ABL gene (translocated from chromosome 9); this fusion gene BCR-ABL with its elevated tyrosine kinase activity must to be central to the pathogenesis of these disorders. Three different breakpoint cluster regions are discerned within the BCR gene on chromosome 22: M-bcr, m-bcr, and mu-bcr. Ph + leukemia cell lines are important tools in this research area. More than 20 ALL-and more than 40 CML-derived Ph + leukemia cell lines have been described. Furthermore, three Ph + B-lymphoblastoid cell lines, established from patients with Ph + ALL or CML, are available. Molecular analysis has documented BCR-ABL fusion genes in three apparently Ph chromosome-negative cell lines, all three derived from CML. Nearly all Ph + ALL cell lines have the m-bcr e1-a2 fusion gene (only two ALL cell lines have a b3-a2 fusion) whereas all CML cell lines, but one carry the M-bcr b2-a2, b3-a2 or both hybrids. The mu-bcr e19-a2 has been detected in one CML cell line. Four cell lines display a three-way translocation involving chromosomes 9, 22 and a third chromosome. Additional Ph chromosomes (up to five) have been found in four Ph + ALL cell lines and in 18 CML cell lines; though in some cell lines the extra Ph chromosome(s) might be caused by the polyploidy (tri- and tetraploidy) of the cells. Another modus to acquire additional copies of the BCR-ABL fusion gene is the formation of tandem repeats of the BCR-ABL hybrid as seen in CML cell line K-562. Both mechanisms, selective multiplication of the der(22) chromosome and tandem replication of the fusion gene BCR-ABL, presumably lead to enhanced levels of the fusion protein and its tyrosine kinase activity (genetic dosage effect). The availability of a panel of Ph + cell lines as highly informative leukemia models offers the unique opportunity to analyze the pathobiology of these malignancies and the role of the Ph chromosome in leukemogenesis.
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PMID:Leukemia cell lines: in vitro models for the study of Philadelphia chromosome-positive leukemia. 1007 Oct 72


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