Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023473 (chronic myeloid leukemia)
 18,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A number of protooncogenes have been implicated in human tumorigenesis. The ABL oncogene is consistently rearranged and activated as a consequence of the translocation t(9;22) that gives rise to the Philadelphia chromosome in chronic myeloid leukemia and in some cases of acute lymphoblastic leukemia. Here we describe rearrangement of ABL in a different type of malignancy. The glioblastoma cell line A172 lacks germline alleles of ABL. A recombination event, presumably followed by a duplication, has created two ABL alleles in which exon 11 is joined to chromosome 16 sequences. Although the main body of ABL exons was still present, two considerably shortened ABL mRNAs of 3.8 and 2.8 kilobases were detected; the 3.8-kilobase mRNA hybridized exclusively to an exon IB probe. Neither mRNA hybridized to an ABL probe encompassing part of the tyrosine kinase domain. Thus, the cell line A172 is able to survive in the absence of a functional ABL gene product, indicating that the role of ABL is unlikely to be "housekeeping."
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PMID:Rearrangement of the human ABL oncogene in a glioblastoma. 233 39

The Philadelphia (Ph1) chromosome (22q-), found in more than 90% of patients with chronic myeloid leukemia (CML), is one part of a reciprocal translocation, t(9;22) (q34;q11), in which the oncogene c-abl moves from 9q34 to 22q11. The translocation results in the translation of an aberrant abl-related protein with tyrosine kinase activity. Genetically active genes are known to have chromatin which is hypersensitive to deoxyribonuclease I (DNase I) and to be hypomethylated. Using an in situ nick translation technique on metaphase chromosomes, we have examined DNase I sensitivity and methylation status at the breakpoints 9q34 and 22q11 in bone marrow cells from controls (two cases) and CML patients (three cases). In CML cells DNase I sensitivity was significantly increased, at both breakpoints, in the translocated chromosomes compared with their normal homologues in CML cells and with both homologues in control marrows. A hypermethylated site, seen at 22q11 in normal 22s was hypomethylated on 22q-. The 9q34 region was hypomethylated in normal and translocated chromosomes. DNase I sensitivity, seen at 22q13 in CML cells, was lost following translocation in one of three cases. This technique demonstrates alterations in chromatin conformation and methylation status at translocation breakpoints which may be related to acquired genetic activity at one or both of these sites.
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PMID:Possible evidence for acquired genetic activity at both chromosomal breakpoints of the Philadelphia translocation in chronic myeloid leukemia. 238 79

The hallmarks of chronic myelogenous leukemia (CML) include the Philadelphia chromosome (Ph) translocation [t (9;22)(q34;q11)] and consistent molecular genetic aberrations: a break within a restricted 5.8 kb DNA segment, bcr, on chromosome 22q11; transposition of the c-abl protooncogene from chromosome 9q34 to 22q11; and formation of a hybrid bar-abl gene encoding an abnormal 210 Kd bcr-abl protein with augmented tyrosine kinase enzymatic activity. These molecular phenomena may occur even in the absence of cytogenetic evidence of the Ph translocation. They are highly specific and sensitive markers for CML, and are presumed to play a significant role in the pathogenesis of this malignancy. Surprisingly, we have encountered 11 patients who lacked the Ph translocation, bcr rearrangement, and (in the four patients with available mRNA) a bcr-abl message, and yet had a disease phenotype at diagnosis that was a morphologic facsimile of classic chronic phase CML. These patients presented with high white blood cell counts, neutrophilia, occasional basophilia, splenomegaly, and a hypercellular bone marrow with granulocytic hyperplasia and a left shift in myeloid maturation. Despite the striking resemblance between the early stages of bcr-negative and bcr-positive CML, disease progression manifests distinctly in these two disorders. In contrast to the blastic transformation that inevitably complicates bcr-positive CML, the natural history of our 11 Ph-negative, bcr-negative CML patients was characterized by increasing leukemia burden with leukocytosis, pronounced organomegaly, extramedullary infiltrates, and eventual bone marrow failure (anemia and thrombocytopenia) without marked increases in blast cells. Our current observations suggest that a chronic myeloid leukemia process can develop without associated changes in the bcr or c-abl genes. Although the initial phase of this disease is indistinguishable from CML, the presence or absence of molecular markers may aid in the prediction of the clinical course of Ph-negative CML.
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PMID:Philadelphia chromosome-negative chronic myelogenous leukemia without breakpoint cluster region rearrangement: a chronic myeloid leukemia with a distinct clinical course. 240 27

Antibodies against phosphotyrosine are a powerful tool with which to identify proteins phosphorylated on tyrosine residues, such as viral oncogene-encoded transforming proteins and their cellular protein substrates. Probed on human leukemia cell lines, phosphotyrosine antibodies recognized a 210,000-molecular-weight protein (p210) in K562 cells, a cell line derived from a Philadelphia (Ph)'-positive chronic myelogenous leukemia (CML), but recognized no protein in control Ph'-negative non-CML leukemia cells. The p210 protein was also recognized by antisera against v-abl-encoded polypeptides and displayed kinase activity, phosphorylating itself on tyrosine, in an immunocomplex kinase assay. These data are consistent with reported findings of the expression of a recombined bcr-abl gene in Ph'-positive CML cells, leading to the synthesis of an altered p210c-abl protein endowed with tyrosine kinase activity. Phosphotyrosine antibodies also detected the expression of the p210c-abl protein in fresh bone marrow cells harvested from CML patients in blast crisis. Besides the p210c-abl protein kinase, phosphotyrosine antibodies recognized other proteins with molecular weights of 110,000, 68,000, and 36,000 (p110, p68, and p36) in K562 cells. When [gamma-32P]ATP was added to nonionic detergent-extracted cells, these proteins became phosphorylated on tyrosine, as confirmed by phosphoamino acid analysis. A comparison with fibroblasts transformed by the v-abl, v-src, and v-fps oncogenes suggested the identity of the p36 protein with the common 36-kilodalton protein substrate of viral oncogene-encoded tyrosine kinases. Enhanced tyrosine phosphorylation of cellular proteins is thus a feature shared by cells transformed by v-abl and cells expressing a rearranged bcr-abl gene.
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PMID:Phosphotyrosine antibodies identify the p210c-abl tyrosine kinase and proteins phosphorylated on tyrosine in human chronic myelogenous leukemia cells. 243 Dec 86

Human chronic myelogenous leukemia cell line K-562 expresses the bcr/c-abl fusion protein which is an active protein tyrosine kinase. Multiple tyrosine-phosphorylated proteins were detected in K-562 cells by immunoblotting with a high-affinity anti-phosphotyrosine antibody. When K-562 cells were induced with hemin to progress through the erythroid differentiation pathway, reduction in the levels of these tyrosine-phosphorylated proteins was observed. This reduction in tyrosine-phosphorylated proteins was not found in another chronic myelogenous leukemia cell line which could not be induced to differentiate by hemin. This and other observations established that the reduction in protein tyrosine phosphorylation is a specific differentiation response. The bcr/c-abl protein synthesis was reduced in hemin-treated K-562 cells. Thus, erythroid differentiation of K-562 cells reduces the level of the bcr/c-abl tyrosine kinase and the phosphotyrosine content of its substrate proteins.
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PMID:Reduction in protein tyrosine phosphorylation during differentiation of human leukemia cell line K-562. 244 May 57

The great majority of patients with chronic myeloid leukaemia (CML) have a Philadelphia (Ph) chromosome which has proved at molecular level to be associated with the production of chimeric BCR-ABL gene which in turn is expressed as a fusion protein (P210) with tyrosine kinase activity. An equivalent but somewhat smaller chimeric gene and fusion protein (P190) is found in some cases of Ph-positive acute leukaemia. Though the consistency of these abnormal findings in patients with Ph-positive leukaemia is strong evidence for their pathogenetic role, there are still many unanswered questions.
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PMID:Recent advances in molecular biology of chronic myeloid leukaemia: is the pathogenetic puzzle approaching solution? 249 82

An altered c-abl protein (P210) bearing increased tyrosine kinase activity represents the product of the hybrid bcr/c-abl gene arising as a consequence of the Philadelphia (Ph1) chromosome translocation, the consistent cytogenetic abnormality of chronic myelogenous leukemia (CML). Although the chronic phase of this disease is substantially characterized by a marked proliferation of myeloid cells, the Ph1 translocation occurs in an early multipotent stem cell, giving rise to both myeloid and lymphoid cell lineages. Here we show that P210 bcr/abl protein expression varies greatly in different Ph1 chromosome positive B-lymphoid cell lines obtained from Epstein-Barr virus-transformed lymphocytes of a CML patient in the chronic phase. In addition Ph1 positive and Ph1 negative lymphoid cell lines obtained from the same patient were tested for a number of biological properties including the immunophenotype, the capacity to grow in soft agar and possible tumorigenicity in nude mice. No differences were found.
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PMID:Expression of the hybrid P210 bcr/abl protein in Philadelphia chromosome positive B-lymphoid cell lines. 251 Oct 93

The c-fms protooncogene encodes the receptor for the colony-stimulating factor 1 of macrophages. Its transforming counterpart, the v-fms oncogene has previously been recognized as the transforming gene of the McDonough strain of feline sarcoma virus. We have isolated rabbit antisera against a 115-kDa recombinant polypeptide containing the 926 carboxy-terminal amino acids of the v-fms protein. All antibodies recognized the cytoplasmic domain of the v-fms protein, which is 95% homologous to the corresponding domain of human c-fms proteins. These sera were applied in a survey of various human cancer cell lines, such as peripheral blood mononuclear (HL60) and choriocarcinoma (BeWo) cells, as well as leukemic cells from 58 patients with acute myelocytic, chronic myelocytic or acute lymphocytic leukemias (AML, CML, ALL). Significantly enhanced levels of fms-specific tyrosine kinase activity were detected in 12-O-tetradecanoylphorbol-13-acetate-induced HL60 and in BeWo cells, and in 7 out of 24 samples from AML patients, whereas no activity could be detected in 9 ALL or in 25 CML cell preparations. The AML cells were classified according to the FAB criteria. The highest incidence of increased fms activity was found in cells assigned to the M4 class (four out of five cases). While no activity was found in material belonging to FAB classes M2 or M3, one of the two cases of the M5 class was kinase-positive. Interestingly, two out of seven cases of the M1 class cells exhibited enhanced levels of fms kinase. These data suggest that the determination of the fms kinase may be useful to subdivide the M1 class of the FAB classification into monocytic and non-monocytic precursor leukemia cells.
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PMID:Detection of fms-oncogene-specific tyrosine kinase activity in human leukemia cells. 252 17

The bcr gene plays a critical role in the pathogenesis of two human leukemias associated with the Philadelphia chromosome: chronic myelogenous leukemia (CML) and acute lymphoblastic leukemia (ALL). In both instances a chimeric gene, formed between bcr and the abl protooncogene, results in expression of fused bcr-abl proteins with tyrosine kinase activity. There is controversy regarding the normal gene products of bcr. We investigated this problem by several techniques and found proteins of 190/185, 155, 135, 125, 108, 83 and 47 kDa in several human cell lines by immunoprecipitation with two distinct site-directed anti-bcr antibodies termed anti-bcr(738-753) and anti-bcr(898-911). The 190/185, 155, 125 and 108 kDa proteins were consistently detected by anti-bcr(898-911) antibodies by immunoblotting. Antibodies pre-reacted with excess bcr peptide did not detect these proteins. These proteins were labeled with [32P]orthophosphate in vivo and in vitro by [gamma 32P]ATP in immune complex kinase assays performed with anti-bcr antibodies indicating that these proteins are phosphorproteins. Following labeling in kinase assays, phosphoamino acid analyses detected both phosphoserine and phosphothreonine. In structural studies using one dimensional peptide maps derived by partial V8 protease treatment, the 185, 155, 135, 125 and 108 kDa proteins shared several peptide fragments but contained unique fragments as well. Similarly 2-dimensional maps of proteins labeled in the kinase assay exhaustively digested with trypsin, revealed homology between the 155, 135, 125, 108, and 83 kDa proteins. bcr proteins sedimented in glycerol gradients as putative complexes detected in the cytoplasm of the cell. A 47 kDa protein as well as the recently identified Ph-P53 protein appeared to be associated with bcr proteins based on their co-sedimentation in glycerol gradients and co-immunoprecipitation with several different anti-bcr antibodies. None of the proteins exhibited a precursor-product relationship in pulse-chase experiments conducted with [35S]methionine. We conclude that human cells express several different bcr gene products ranging in size from 190 to 83 kDa, and that these proteins can form specific intracellular cytoplasmic complexes with other cellular proteins.
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PMID:Characterization of bcr gene products in hematopoietic cells. 264 52

The tyrosine kinase P210 is the gene product of the rearranged BCR-ABL locus on the Philadelphia chromosome (Ph1), which is found in leukemic cells of patients with chronic myelogenous leukemia. It has a weakly oncogenic effect in immature murine hematopoietic cells and does not transform NIH 3T3 cells. We have found that P210 has a strikingly different effect in Rat-1 cells, another line of established rodent fibroblasts. Stable expression of P210 in Rat-1 cells caused a distinct morphological change and conferred both tumorigenicity and capacity for anchorage-independent growth. The introduction of v-myc into Rat-1 cells expressing P210 led to complete morphological transformation and enhanced tumorigenicity. No such interaction took place in NIH 3T3 cells. Thus, Rat-1 cells can be used to detect cooperation between BCR-ABL and other oncogenes and may prove useful for the identification of secondary oncogenic events in chronic myelogenous leukemia.
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PMID:The BCR-ABL oncogene transforms Rat-1 cells and cooperates with v-myc. 272 97


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