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)

The molecular basis of the Philadelphia chromosome (Ph1) is a structurally altered c-abl (bcr/abl) gene which encodes an abnormally large protein with protein tyrosine kinase activity. Herbimycin A, an inhibitor of tyrosine kinase, preferentially inhibited the growth of Ph1-positive acute lymphoid leukemia (ALL) cell lines, as well as Ph1-positive chronic myeloid leukemia (CML) cell lines. Although noncytotoxic concentrations of herbimycin A induced erythroid differentiation of two CML-derived cell lines, K562 and KU812, in a previous study, the differentiation-inducing effect of herbimycin A on Ph1-positive ALL cell lines was less strong. Herbimycin A enhanced some differentiation-associated properties of one Ph1-positive ALL cell line, L2, but the effect of herbimycin A on the other Ph1-positive ALL cell lines was cytotoxic rather than cytostatic (differentiation-inducing). Several derivatives of herbimycin A were synthesized and their effects on the cell proliferation of Ph1-positive CML and ALL cell lines were examined. The sensitivities of the Ph1-positive cell lines to herbimycin A derivatives were different from the data on the rat kidney cell line infected with Rous sarcoma virus (v-src) derived from a previous study, suggesting bcr/abl kinase may differ in sensitivity from other tyrosine kinases. Moreover, the sensitivities of the ALL cell lines were not the same as those of the CML cell lines. These results suggest that a specific inhibitor of bcr/abl kinase could be an effective antileukemic agent against Ph1-positive CML or ALL.
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PMID:Effects of herbimycin A and its derivatives on growth and differentiation of Ph1-positive acute lymphoid leukemia cell lines. 813 88

Ph+ chronic myelogenous leukemia (CML) is associated with the reciprocal translocation between chromosomes 9 and 22 culminating in the production of the chimeric p210bcr/abl protein possessing elevated protein tyrosine kinase activity relative to the normal c-abl tyrosine kinase. Our recent studies have revealed subtle differences in the growth, phenotypic and morphologic characteristics of subpopulations of primary lin- Ph+ chronic phase CML blasts and comparable primary normal blasts. In an attempt to correlate these biologic abnormalities and the presence of the p210bcr/abl protein, we initiated studies to identify differences in proteins constitutively phosphorylated on tyrosine in whole cell lysates of comparable primary early blast subpopulations derived from normal and Ph+ chronic phase CML marrows. Immunoblotting with anti-P-tyr Abs demonstrated a prominent 62 kDa phosphotyrosyl protein (pp62) constitutively present in 11/11 Ph+ chronic phase linblasts while being virtually undetectable in equivalent amounts of protein derived from 15/15 and 2/2 comparable normal and Ph-negative chronic phase blast populations, respectively. Immunoblotting with an Ab reportedly specific for the ras GTPase activating protein (GAP) associated p62 protein revealed that the pp62 present in CML blasts is not immunologically related to the former protein. Although the identity of the pp62 is presently not known, its prominent presence in chronic phase CML blasts, in which the only known molecular abnormality is putatively the p210bcr/abl protein, strongly suggests that it may be a critical p210bcr/abl substrate involved in an early stage of expansion of the Ph+ clone.
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PMID:A 62-kilodalton tyrosine phosphoprotein constitutively present in primary chronic phase chronic myelogenous leukemia enriched lineage negative blast populations. 815 67

The phosphorylation of proteins at tyrosine residues is critical in cellular signal transduction and neoplastic transformation. These mechanisms are regulated by the activities of both protein-tyrosine kinases and protein-tyrosine phosphatases. Recent studies have identified a novel protein-tyrosine phosphatase, termed Syp, that is widely expressed in various tissues. Syp encodes a cytoplasmic phosphatase that contains two Src homology 2 (SH2) domains. Since SH2 domains have been shown to target the association of signal-transducing molecules to activated tyrosine kinases, experiments were performed to determine whether Syp might form specific complexes with p210bcr-abl, a fusion protein believed to be involved in the pathogenesis of chronic myelogenous leukemia and, thus, possibly alter or mediate p210bcr-abl tyrosine kinase activity. We found that Syp was highly and constitutively tyrosine phosphorylated in three different murine cell lines transfected with a p210bcr-abl expression vector. Furthermore, p210bcr-abl, Syp, and Grb2 formed stable complexes in BCR-ABL-expressing cells. Complex formation between p210bcr-abl and Syp was mediated in vitro by the NH2-terminal SH2 domain of Syp. Last, p210bcr-abl tyrosine kinase was effectively dephosphorylated by Syp in vitro. These results suggest an interaction between Syp and BCR-ABL protein, which might play a role in cellular transformation of BCR-ABL.
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PMID:SH2-containing phosphotyrosine phosphatase Syp is a target of p210bcr-abl tyrosine kinase. 819 76

The p210bcr/abl tyrosine kinase appears to be responsible for initiating and maintaining the leukemic phenotype in chronic myelogenous leukemia (CML) patients. p21ras-p120GAP interactions play a central role in transducing mitogenic signals. Therefore, we investigated whether p21ras and p120GAP are regulated by p210bcr/abl, and whether this activation is functionally significant for CML cell proliferation. We report that transient expression of p210bcr/abl in fibroblast-like cells induces simultaneous activation of p21ras and inhibition of GTPase-promoting activity of p120GAP, and confirm these data showing that downregulation of p210bcr/abl expression in CML cells with bcr/abl antisense oligodeoxynucleotides induces both inhibition of p21ras activation and stimulation of GTPase-promoting activity of p120GAP. Tyrosine phosphorylation of two p120GAP-associated proteins, p190 and p62, which may affect p120GAP activity, also depends on p210bcr/abl tyrosine kinase expression. Direct dependence of these effects on the kinase activity is proven in experiments in which expression of c-MYB protein in fibroblast-like cells or downregulation of c-MYB expression resulting in analogous inhibition of CML cell proliferation does not result in the same changes. Use of specific antisense oligodeoxynucleotides to downregulate p21ras expression revealed a requirement for functional p21ras in the proliferation of Philadelphia chromosome-positive CML primary cells. Thus, the p210bcr/abl-dependent regulation of p120GAP activity is responsible, in part, for the maintenance of p21ras in the active GTP-bound form, a crucial requirement for CML cell proliferation.
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PMID:Negative regulation of p120GAP GTPase promoting activity by p210bcr/abl: implication for RAS-dependent Philadelphia chromosome positive cell growth. 819 13

The Philadelphia chromosome, detected in virtually all cases of chronic myelogenous leukemia, is formed by a reciprocal translocation between chromosomes 9 and 22 that fuses BCR encoded sequences upstream of exon 2 of c-ABL. This oncogene produces a fusion protein, p210BCR-ABL, in which the ABL tyrosine kinase activity is elevated. This elevated kinase activity is essential for transformation, but the mechanisms involved are unknown. To investigate p210BCR-ABL function we constructed a model system in which the tyrosine kinase activity of p210BCR-ABL was inducible. Two amino acid substitutions, Arg to His at amino acid 457 and Tyr to His at amino acid 469 of c-abl, modeled on mutations known to render v-src temperature-sensitive for tyrosine kinase activity, were introduced into p210BCR-ABL. This mutant was characterized in an IL-3 growth factor dependent murine myeloid cell line, 32Dc13. Cell lines expressing the temperature-sensitive mutant remained factor dependent at the non-permissive temperature, but at the permissive temperature displayed a marked reduction in cell death in the absence of growth factor and an exaggerated proliferative response to low levels of IL-3. Both the kinase activity of the mutant and the levels of tyrosine phosphorylated proteins are increased in the temperature-sensitive mutant at the permissive temperature. Further, tyrosine phosphorylation of potential substrates of the p210BCR-ABL tyrosine kinase, p120 rasGAP and its associated proteins of p190 and p62, only occurs at the permissive temperature in cells expressing the temperature-sensitive mutant.
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PMID:Use of a temperature-sensitive mutant to define the biological effects of the p210BCR-ABL tyrosine kinase on proliferation of a factor-dependent murine myeloid cell line. 830 74

Previously, p210bcr-abl has been detected in Philadelphia-chromosome-positive chronic myelogenous leukemia (CML) blast crisis and established cells originating from blasts. It has not been detected in mature granulocytes in the chronic phase. Protein degradation tends to occur during protein extraction, due to the activities of protease and phosphatase within these cells. Protein was, therefore, extracted in a cell lysis buffer containing alpha 1-antitrypsin and a high concentration of Na3VO4 as inhibitors. In mature granulocytes in the chronic phase, p210bcr-abl was detected and the level of tyrosine phosphorylation estimated by immunoblotting, using the enzyme-labeled antibody method with anti-c-abl and anti-phosphotyrosine antibodies. p210bcr-abl was phosphorylated on tyrosine residues in blast crisis cells and K562 cells derived from CML blast crisis, whereas it was dephosphorylated in mature granulocytes from chronic phase CML patients. This suggests that p210bcr-abl in mature granulocytes has no tyrosine kinase activity, or it is extremely weak, and dephosphorylation of p210bcr-abl is associated with differential maturation of immature cells in the chronic phase of CML.
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PMID:Detection of P210bcr-abl in mature granulocytes from Ph1-positive chronic myelogenous leukemia patients by an immunoblotting method. 835 Jun 17

We have identified and partially characterized a gene located on chromosome 22, band q11, centromeric of the chronic myelogenous leukemia breakpoint region. A number of overlapping cDNAs were isolated from this locus and the largest of 1.8 kb was sequenced. Its deduced amino acid sequence shows homology to the SH2 domains of protein tyrosine kinases such as FER, and is strikingly similar to the cellular part of the v-crk oncogene product. We identified one SH2 and two SH3 domains within the 303 amino acid open reading frame of this crk-like gene, CRKL. The CRKL gene product is predicted to have a molecular mass of 36 kDa. In addition, we demonstrate that this gene does not represent the human homolog of v-crk but rather a novel gene potentially capable of mediating the transduction of intracellular signals.
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PMID:Isolation and chromosomal localization of CRKL, a human crk-like gene. 836 59

Accumulating evidence indicates that the activation of cellular oncogenes is a cause of some human cancers. ErbB-1, erbB-2 and abl oncogenes encoding tyrosine kinases, ras oncogenes encoding GTP binding proteins and myc oncogenes whose functions are not well understood are some examples. Therefore, agents which inhibit the activity of these oncogene products may provide new means to overcome certain human tumors. Herbimycin A and tyrphostins have been found and developed as inhibitors of tyrosine kinases and the effectiveness of these agents against tumors of Ph1-positive leukemia (CML, ALL) or squamous cell carcinomas has been reported. Although specific inhibitors of ras or myc oncogene products have not yet been described, recent studies on the processing of Ras proteins toward the cell membrane provide a strategy to search for inhibitors of ras functions.
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PMID:[Anticancer agents targeting oncogene products]. 837 83

Chronic myelogenous leukemia (CML) is characterized by a specific chromosomal translocation occurring between the long arms of chromosomes 9 and 22 resulting in a fusion product, p210 BCR/ABL, which has elevated tyrosine kinase activity. Expression of p210 BCR/ABL in murine interleukin-3 (IL-3)--dependent cell lines typically converts these cell lines to factor-independence by a non-autocrine mechanism. The IL-3 receptor is believed to function in part by activating a receptor-associated tyrosine kinase, leading to the hypothesis that p210 BCR/ABL may induce factor-independence of myeloid cells by constitutively phosphorylating some common signal-transducing proteins that normally would be phosphorylated on tyrosine residues in response to IL-3. p210 BCR/ABL subclones were constructed from an IL-3-dependent murine myeloid cell line, 32Dcl3, by transfection of a plasmid containing a full-length p210 BCR/ABL cDNA. Following transfection, the cells became completely factor-independent within 3 weeks. We examined the effects of p210 BCR/ABL and IL-3 on the pattern of tyrosine phosphorylation of cellular proteins in 32Dcl3 cells using one- and two-dimensional antiphosphotyrosine immunoblotting. WEHI-3B conditioned media (WEHI-CM) was used as a source of IL-3. The introduction of p210 BCR/ABL results in constitutively increased levels of tyrosine phosphorylation of more than 20 new proteins, while WEHI-CM induced transient tyrosine phosphorylation of 6 to 10 new proteins. Using two-dimensional immunoblots to examine phosphoproteins, four categories could be identified: (1) proteins that are inducibly tyrosine phosphorylated in response to WEHI-CM in 32Dcl3 cells only, (2) proteins inducibly tyrosine phosphorylated by WEHI-CM only in p210 BCR/ABL+ cells, (3) proteins that are inducibly tyrosine phosphorylated in response to WEHI-CM in both 32Dcl3 cells and p210 BCR/ABL+ cells, and (4) proteins inducibly tyrosine phosphorylated in response to WEHI-CM and constitutively phosphorylated in the presence of p210 BCR/ABL. We have identified one of the proteins in category 4 as p42 mitogen-activated protein (MAP) kinase (ERK2). Overall, however, we found that the signal transduction pathways of IL-3 and BCR/ABL are strikingly different, suggesting that most of the immediate substrates of the IL-3 receptor-activated tyrosine kinase and p210 BCR/ABL kinase are different. Convergence of signaling pathways at p42 MAP kinase is of interest since activation of this kinase has been linked to mitogenesis in many systems. Identification of the overlapping proteins of both IL-3 signal transduction in 32Dcl3 cells and p210 BCR/ABL+ cells may help explain the growth-promoting effects of this oncogene.
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PMID:Interleukin-3 and p210 BCR/ABL activate both unique and overlapping pathways of signal transduction in a factor-dependent myeloid cell line. 840 19

P210 BCR/ABL is a chimeric oncogene implicated in the pathogenesis of chronic myelogenous leukemia. BCR sequences have been shown to be required for activation of the tyrosine kinase and transforming functions of BCR/ABL. In this work, we show that two other structural requirements for full transforming activity of P210 BCR/ABL include a functional tyrosine kinase and the presence of tyrosine 1294, a site of autophosphorylation within the tyrosine kinase domain. Replacement of tyrosine 1294 with phenylalanine (1294F) greatly diminishes the transforming activity of BCR/ABL without affecting the specific activity of the protein tyrosine kinase. Expression of an exogenous myc gene in fibroblasts partially complements the transforming capacity of mutant P210 BCR/ABL (1294F). Surprisingly, tyrosine 1294 is not required for efficient induction of growth factor-independence in hematopoietic cell lines by P210 BCR/ABL. These results suggest that autophosphorylation at tyrosine 1294 may be important for recognition and phosphorylation of cellular substrates in the pathway of transformation, but it is not critical for mediating the events which lead to growth factor independence.
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PMID:SH1 domain autophosphorylation of P210 BCR/ABL is required for transformation but not growth factor independence. 844 9


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