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)

Two bcr/abl fusion gene products with tyrosine kinase activity have been found in two phenotypes of Philadelphia chromosome (Ph1)-positive leukemia. P210bcr/abl (P210) is associated with Ph1-positive chronic myelogenous leukemia (CML), while P190bcr/abl is associated with Ph1-positive acute leukemia. We compared the susceptibility of 32Pi-labeled P210 from K-562 cells and P190 from MR-87 cells to protein tyrosine phosphatase (PTPase). PTPase, present in the lysate of mature granulocytes from CML patients as well as in the lysate of these cells from normal subjects, effectively dephosphorylated the CML-associated P210 and the acute leukemia associated P190. This PTPase activity was specifically inhibited by ZnCl2; it was not present in lymphocyte lysates, and was not inhibited by neutralization with anti-CD45 antibody. Since P210 and P190 were equally sensitive to the PTPase, the difference in leukemic phenotypes associated with the expression of these two tyrosine kinases cannot be explained by the differential dephosphorylation of P210 and P190.
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PMID:Two bcr/abl fusion gene products, P210bcr/abl and P190bcr/abl, are equally sensitive to the protein tyrosine phosphatase of mature granulocytes. 179 29

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

alpha-Interferon (IFN-alpha) is important in the management of chronic myelogenous leukemia (CML). The P210bcr/abl fusion protein, with enhanced tyrosine kinase activity, is implicated in the pathogenesis and progression of the disease. To elucidate the inhibitory mechanism of IFN-alpha on CML cell proliferation, we studied the effect of IFN-alpha on P210bcr/abl in K-562 cells. The phosphorylated level of P210bcr/abl was not altered by treatment with IFN-alpha alone despite its inhibiting cell proliferation. However, when K-562 cells were treated with either a low (5 x 10(2) U/ml) or high (10(4) U/ml) concentration of IFN-alpha in the presence of hemin, P210bcr/abl protein activity decreased through reduction of in vivo phosphorylation, but not through inhibition of de novo protein synthesis. Furthermore, hemoglobin content was increased by IFN-alpha at both low and high concentrations in tandem with hemin-induced erythroid differentiation and the change in P210bcr/abl. These results demonstrate that IFN-alpha synergises hemin-mediated erythroid differentiation as it reduces the in vivo tyrosine phosphorylation of P210bcr/abl in K-562 cells.
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PMID:Alpha-interferon reduces in vivo phosphorylation of P210bcr/abl protein during hemin-induced erythroid differentiation of K-562 cells. 199 6

Tyrosine phosphorylation is important in the transmission of growth and differentiation signals; known tyrosine kinases include several oncoproteins and growth factor receptors. Interestingly, some differentiated cell types, such as erythrocytes and platelets contain high amounts of phosphotyrosine. We analyzed tyrosine kinases expressed in the K-562 chronic myelogenous leukemia cell line, which has a bipotential erythroid and megakaryoblastoid differentiation capacity. Analysis of 359 polymerase chain reaction-amplified cDNA clones led to the identification of 14 different tyrosine kinase-related sequences (JTK1-14). Two of the clones (JTK2 and JTK4) represent unusual members of the fibroblast growth factor receptor gene family, and the clones JTK5, JTK11, and JTK14 may also belong to the family of receptor tyrosine kinases but lack a close relationship to any known tyrosine kinase. Each of these different genes has its own characteristic expression pattern in K-562 cells and several other human tumor cell lines. In addition, the JTK11 and JTK14 mRNAs are induced during the megakaryoblastoid differentiation of K-562 cells. These tyrosine kinases may have a role in the differentiation of megakaryoblasts or in the physiology of platelets.
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PMID:Putative tyrosine kinases expressed in K-562 human leukemia cells. 224 64

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

An altered c-abl gene product (P210bcr-abl) possessing associated tyrosine protein kinase activity was recently been reported in several blast chronic myelogenous leukemia (CML) cell lines. We have examined different morphological types of leukocytes directly obtained from patients at the blast crisis stage of CML for expression of P210bcr-abl tyrosine protein kinase activity. Phosphorylation of P210bcr-abl in an immune complex kinase assay using an anti-v-abl peptide serum was observed in blast cells from four Philadelphia chromosome (Ph1)-positive CML patients in blast crisis. P210bcr-abl protein kinase activity was detected regardless of whether the blast cells were of myeloid, lymphoid, or undifferentiated morphology. P210bcr-abl protein kinase activity was not detected in immune complexes either from leukocytes of four Ph1-negative CML patients in blast crisis, of five acute myelogenous leukemia patients, or in the promyelocytic cell line HL-60. Mature myeloid cells are associated with an inhibitory factor for not only P210bcr-abl protein kinase activity, but also protein kinases in general. Therefore, analyses of Ph1-positive benign phase CML myeloid cells, the majority of which are well differentiated, could not be successfully performed. The inhibition of P210bcr-abl protein kinase activity is not a specific property of mature cells from CML patients since granulocytes from a normal volunteer also demonstrated a similar effect. However, extracts of Ph1-positive cultured B-lymphocytes from a patient in benign phase demonstrated active P210bcr-abl protein indicating that the P210bcr-abl protein is expressed in an enzymatically active form in the earlier phases of CML. In addition to the previously reported P210 and P190 abl-related proteins, a novel Mr 53,000 protein was found to undergo phosphorylation at serine and tyrosine in immune complex kinase assays of two blast crisis CML cell lines (K562 and EM2) and in samples from blast crisis patients in which P210bcr-abl was detected. Peptide mapping by the Cleveland technique suggested that Mr 53,000 protein is unrelated to P210bcr-abl. Immune complex kinase assays of K562 cells with an anti-src serum (GD-11) yielded active c-src kinase and a Mr 50,000 phosphorylated protein, both of which were resistant to alkaline hydrolysis. Peptide mapping suggested that Mr 53,000 protein is related to Mr 50,000 protein which is precipitated with P210bcr-abl as an Mr 300,000 protein complex.
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PMID:Analysis of P210bcr-abl tyrosine protein kinase activity in various subtypes of Philadelphia chromosome-positive cells from chronic myelogenous leukemia patients. 243 23

An aberrant p210BCR-ABL protein that possesses constitutive protein-tyrosine kinase activity is presumed to be involved in the development of the neoplastic phenotype in chronic myelogenous leukemia (CML). Using a highly specific antibody against phosphotyrosine, we have isolated the tyrosine-phosphorylated p210BCR-ABL and several other proteins containing phosphotyrosine from a variety of CML cell lines. p210BCR-ABL isolated by the monoclonal anti-phosphotyrosine antibody possessed protein-tyrosine kinase activity in vitro comparable to that of the p210BCR-ABL isolated by antibody to a specific peptide sequence in the ABL protein-tyrosine kinase. Other prominent proteins containing phosphorylated tyrosine residues were observed at 185, 150, 120, 105, 63, 56, 36, and 32 kDa, and less prominent proteins were observed at 195, 155, 94, 53, 40, and less than 29 kDa. Staphylococcal V8 peptide mapping indicated that proteins of similar molecular weights were highly homologous to each other across cell lines, despite the diverse hematopoietic lineages of these cells and the genetic heterogeneity of the patients from whom the CML cell lines were derived. Phosphopeptide mapping also revealed that these proteins were distinct from each other as well as from p210BCR-ABL. Because virtually identical phosphotyrosine-containing proteins were found in peripheral blood leukocytes taken directly from CML patients, these proteins are not an artifact of long-term tissue culture but appear to be an integral part of the CML phenotype.
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PMID:Cell lines and peripheral blood leukocytes derived from individuals with chronic myelogenous leukemia display virtually identical proteins phosphorylated on tyrosine residues. 244 21

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

In chronic granulocytic leukemia (CGL) the Philadelphia translocation results in the production of a novel 210 kDa bcr-abl fusion protein which shows increased tyrosine protein kinase activity in comparison with its normal 145 kDa c-abl counterpart. Using an immunoblotting method and antiphosphotyrosine antibody, we have identified the tyrosine protein kinase substrates present in intact cells from two Philadelphia-positive CGL derived cell lines (K562 and BV173) and compared these with the substrates present in a Philadelphia-negative myeloid cell line (HL60). We have demonstrated an increased number of substrates, particularly of low (less than 110 kDa) molecular weight in the K562 or BV173 cells compared with the HL60 cells. There is virtual identity of the substrates present in the two CGL-derived lines. This work supports the hypothesis that the functional changes present in the bcr-abl 210 kDa protein of CGL results in altered tyrosine phosphorylation of intracellular proteins and that this is of importance in the pathogenesis of CGL.
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PMID:Tyrosine protein kinase substrates in Philadelphia-positive human chronic granulocytic leukemia derived cell lines (K562 and BV173): detection by using an immunoblotting technique. 244 34

P210bcr/abl protein with tyrosine protein kinase has been implicated in the proliferation and differentiation of chronic myelogenous leukemia cells. Using an immunoblotting technique with antiphosphotyrosine (anti-P-Tyr) antibodies, we examined whether P210bcr/abl protein was expressed in chronic phase cells in patients with chronic myelogenous leukemia (CML). We could detect P210bcr/abl protein in blast cells regardless of myeloid or lymphoid lineage but not in chronic phase cells from patients. However, in a patient with both blast cells and chronic phase cells, we could identify the protein only after the enrichment of the blast crisis cells by Percoll gradient centrifugation. When K562 cells were mixed with mature granuloid cells, the P210bcr/abl in K562 cells detected by immunoblotting was decreased. Using phosphotyrosyl proteins in K562 cells as substrates, high phosphotyrosyl (P-Tyr) phosphatase activity was observed, not only in the lysate of chronic phase cells from CML patients but also in the lysate of neutrophils from normal subjects. These findings suggest the possibility that high P-Tyr phosphatase activity prevents the detection of P210bcr/abl in CML cells in the chronic phase. The activity may be characteristic of mature cells and may regulate cellular events through dephosphorylation of P210bcr/abl.
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PMID:Phosphotyrosine phosphatase activity prevents the detection of P210bcr/abl protein in mature cells in chronic myelogenous leukemia even by an immunoblotting technique. 247 29


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