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

The glutathione S-transferases are a group of enzymes involved in the detoxification of a wide range of xenobiotics. Elevation of the level of activity of glutathione S-transferases within the cytosol has been associated with the development of resistance to a number of cytotoxic drugs, including some commonly used in the treatment of leukaemia. In this paper we describe the purification and characterization of an anionic (p class) form of the enzyme from the peripheral blood of patients with acute myeloid leukemia, chronic myeloid leukaemia, and acute lymphocytic leukaemia and the spleen of a patient with chronic lymphocytic leukaemia. We present evidence that the form of enzyme purified closely resembles pi class glutathione S-transferase purified from human placenta. Immunoblotting performed on cytosol from the leukaemic cells from a range of cases of leukaemia at presentation, or on treatment, demonstrated that this form of glutathione S-transferase was the predominant isoenzyme expressed in all cases studied. However, in the limited number of cases studied there was no correlation between the level of expression and response to chemotherapy, suggesting that increased expression of pi class GST is not the sole cause of resistance to bifunctional alkylating agent in human leukaemias.
 ...
PMID:Purification and characterization of a pi class glutathione S-transferase from human leukaemic cells. 226 12

The human multidrug-resistance gene (MDR1) encodes an energy-dependent multidrug efflux protein responsible for the cross-resistance of cultured cells to natural product chemotherapeutic agents such as the anthracyclines and vinca alkaloids. RNA transcript levels were measured in leukemia cells obtained from 15 adult acute nonlymphocytic leukemia (ANLL) cases and 15 cases of chronic myelogenous leukemia (CML). Expression of MDR1 RNA was common in ANLL, and appears to be most frequent in leukemic cells of patients with the poorest response to chemotherapy. Expression of the MDR1 gene was not detectable in the peripheral white blood cells of any of the CML cases during the chronic phase, but was detectable in the immature cells present during this phase of the disease. The cells of the three blastic crisis patients contained detectable levels of MDR1 RNA. These studies support the idea that expression of the MDR1 gene contributes to drug resistance in ANLL, and may play a role in some instances in the drug-resistance of CML in blastic crisis. In contrast, studies of the level of expression of anionic glutathione transferase and DNA polymerase B failed to show any relationship between the RNA transcript levels of these enzymes and responsiveness to chemotherapy.
 ...
PMID:Expression of the multidrug resistance gene in myeloid leukemias. 230 54

We have developed a RIA for erythrocyte acid glutathione S-transferase (GST), which is immunologically identical to major GSTs from other blood cell components, and measured its serum concentrations in various hematological disorders. In some patients with paroxysmal nocturnal hemoglobinuria, chronic myelomonocytic leukemia, chronic myelocytic leukemia, polycythemia vera and myelofibrosis, the concentrations were high. Very high levels were found in 2 of 3 patients with acute lymphocytic leukemia, while acute myelocytic leukemia exhibited a modest increment. No or little increase was seen in aplastic anemia and myelodysplastic syndrome except chronic myelomonocytic leukemia. It is suggested that the measurement of serum acidic GST may be of use as a clinical marker of increased destruction and/or overproduction of blood cells.
 ...
PMID:Radioimmunoassay for erythrocyte acidic GSH S-transferase. 249 36

The Philadelphia chromosome translocation generates a chimeric oncogene, BCR/ABL, which causes chronic myelogenous leukemia (CML). In primary neutrophils from patients with CML, the major novel tyrosine-phosphorylated protein is CRKL, an SH2-SH3-SH3 linker protein which has an overall homology of 60% to CRK, the human homologue of the v-crk oncogene product. Anti-CRKL immunoprecipitates from CML cells, but not normal cells, were found to contain p210BCR/ABL and c-ABL. Several other phosphoproteins were also detected in anti-CRKL immunoprecipitates, one of which has been identified as paxillin, a 68-kDa focal adhesion protein which we have previously shown to be phosphorylated by p210BCR/ABL. Using GST-CRKL fusion proteins, the SH3 domains of CRKL were found to bind c-ABL and p210BCR/ABL, while the SH2 domain of CRKL bound to paxillin, suggesting that CRKL could physically link p210BCR/ABL to paxillin. Paxillin contains three tyrosines in Tyr-X-X-Pro (Y-X-X-P) motifs consistent with amino acid sequences predicted to be optimal for binding to the CRKL-SH2 domain (at positions Tyr-31, Tyr-118, and Tyr-181). Each of these tyrosine residues was mutated to a phenylalanine residue, and in vitro binding assays indicated that paxillin tyrosines at positions 31 and 118, but not 181, are likely to be involved in CRKL-SH2 binding. These results suggest that the p210BCR/ABL oncogene may be physically linked to the focal adhesion-associated protein paxillin in hematopoietic cells by CRKL. This interaction could contribute to the known adhesive defects of CML cells.
 ...
PMID:CRKL links p210BCR/ABL with paxillin in chronic myelogenous leukemia cells. 749 40

We performed cloning and sequence analysis of translocation junctions at 11q- and 22q- (Ph1) chromosomes and the corresponding germline DNAs of a variant Ph1-positive CML with t(9;22;11)(q34;q11;q13). Southern blot analysis using probes for different regions of bcr mapped the translocation break near the 5'-side of bcr exon 4. Cloning, Southern blot analysis and restriction map analysis of both bcr fragments showed that the part of bcr 3'- to the translocation break moved to 11q13. Sequence analysis of the translocation junction on the Ph1 chromosome showed that the translocation break occurred 63 bp upstream of exon 4. Compared to the germline sequence, bcr sequence from the translocated partners showed deletion of seven basepairs at the site of translocation. A probe derived from the 5'-region of the clone isolated from the 11q- chromosome identified clonal rearrangements in the leukemic DNA. Restriction map and sequence analysis showed that this clone consisted of the 3'-half of the glutathione S-transferase Pi (GST-Pi) gene and the 3'-part of bcr. We identified two point mutations in the GST-Pi allele involved in translocation. Northern blot analysis showed that the GST-Pi gene was expressed in the leukemic cells at blast crisis but not at chronic phase; however, no fusion mRNA between GST-Pi and bcr was identified. We did not find any sequence homology between 11q13 DNA and 22q11 DNA around the translocation breakpoints; however, sequences homologous to ALU repeats were identified close to the sites of translocation breaks at 22q11 and 11q13. This study supports our hypothesis that variant Ph1 translocations may occur as primary cytogenetic changes similar to the classical Ph1 translocations.
 ...
PMID:Molecular characterization of a variant Ph1 translocation t(9;22;11) (q34;q11;q13) in chronic myelogenous leukemia (CML) reveals the translocation of the 3'-part of BCR gene to the chromosome band 11q13. 824 27

Recently, we have reported that N2Yc, a Moloney-based retrovirus vector expressing the Yc isoform of rat glutathione S-transferase (GST-Yc), conferred resistance to alkylating agents in mouse NIH-3T3 fibroblasts. In this report, we address the feasibility of using rat GST-Yc somatic gene transfer to confer chemoprotection to the hematopoietic system. Human chronic myelogenous leukemia K-562 cells were efficiently transduced with the N2Yc retrovirus vector and showed a significant increase in the 50% inhibitory concentration of chlorambucil (3.2- to 3.3-fold), mechlorethamine (4.7- to 5.3-fold), and melphalan (2.1- to 2.2-fold). In addition, primary murine clonogenic hematopoietic progenitor cells transduced with the N2Yc vector were significantly more resistant to alkylating agents in vitro than cells transduced with the antisense N2revYc vector. The survival of Yc-transduced hematopoietic colonies at 400 nM mechlorethamine and 4 mu M chlorambucil was 39.4% and 42.6%, respectively, compared to 27.2% and 30.4% for N2revYc-transduced cells. Future experiments will determine the level of chemoprotection achievable in vivo, following transplantation of N2Yc-transduced hematopoietic cells in mice.
 ...
PMID:Retrovirus-mediated gene transfer of rat glutathione S-transferase Yc confers in vitro resistance to alkylating agents in human leukemia cells and in clonogenic mouse hematopoietic progenitor cells. 886 Aug 35

The Philadelphia chromosome translocation generates a chimeric oncogene, BCR/ABL, which causes chronic myelogenous leukemia (CML). In primary leukemic neutrophils from patients with CML, the major tyrosine phosphorylated protein is CRKL, an SH2-SH3-SH3 adapter protein which has an overall homology of 60% to CRK, the human homologue of the v-crk oncogene. In cell lines transformed by BCR/ABL, CRKL was tyrosine phosphorylated, while CRK was not. We looked for changes in CRK- and CRKL-binding proteins in Ba/F3 hematopoietic cell lines which were transformed by BCR/ABL. Anti-CRK II or anti-CRKL immunoprecipitates were probed by far Western blotting with CRK II- or CRKL-GST fusion proteins to display CRK- and CRKL-coprecipitating proteins. There was a striking qualitative difference in the proteins coprecipitating with CRKL and CRK II. In untransformed cells, three major proteins coprecipitated with CRKL, identified as C3G, SOS and c-ABL. Each of these proteins was found to interact with the CRKL-SH3 domains, but not the SH2 domain. After BCR/ABL transformation, the CRKL SH3-domain binding proteins did not change, with the exception that BCR/ABL now coprecipitated with CRKL. Compared to CRKL, very few proteins coprecipitated with CRK II in untransformed, quiescent cells. After BCR/ABL transformation, both the CRKL- and CRK-SH2 domains bound to a new complex of proteins of approximate molecular weight 105-120 kDa. The major protein in this complex was identified as p120CBL. Thus, in these hematopoietic cell lines, CRKL is involved to a greater extent than CRK II in normal signaling pathways that involve c-ABL, C3G and SOS. In BCR/ABL-transformed cells, CRKL but not CRK II, appears to form complexes which potentially link BCR/ABL, c-ABL, C3G, and SOS to the protooncoprotein, p120CBL.
 ...
PMID:The BCR/ABL oncogene alters interaction of the adapter proteins CRKL and CRK with cellular proteins. 906 77

Grb2/Ash and Shc are the adapter proteins that link tyrosine-kinase receptors to Ras and make tyrosine-kinase functionally associated with receptors and Ras in fibroblasts and hematopoietic cells. Grb2/Ash and Shc have the SH3, SH2, or phosphotyrosine binding domains. These domains bind to proteins containing proline-rich regions or tyrosine-phosphorylated proteins and contribute to the association of Grb2/Ash and Shc with other signaling molecules. However, there could remain unidentified signaling molecules that physically and functionally interact with these adapter proteins and have biologically important roles in the signaling pathways. By using the GST fusion protein including the full length of Grb2/Ash, we have found that c-Cbl and an unidentified 135-kD protein (pp135) are associated with Grb2/Ash. We have also found that they become tyrosine-phosphorylated by treatment of a human leukemia cell line, UT-7, with granulocyte-macrophage colony-stimulating factor (GM-CSF). We have purified the pp135 by using GST-Grb2/Ash affinity column and have isolated the full-length complementary DNA (cDNA) encoding the pp135 using a cDNA probe, which was obtained by the degenerate polymerase chain reaction based on a peptide sequence of the purified pp135. The cloned cDNA has 3,958 nucleotides that contain a single long open reading frame of 3,567 nucleotides, encoding a 1,189 amino acid protein with a predicted molecular weight of approximately 133 kD. The deduced amino acid sequence reveals that pp135 is a protein that has one SH2, one SH3, and one proline-rich domain. The pp135, which contains two motifs conserved among the inositol polyphosphate-5-phosphatase proteins, was shown to have the inositol polyphosphate-5-phosphatase activity. The pp135 was revealed to associate constitutively with Grb2/Ash and inducibly with Shc using UT-7 cells stimulated with GM-CSF. In the cell lines derived from human chronic myelogenous leukemia, pp135 was constitutively tyrosine-phosphorylated and associated with Shc and Bcr-Abl. These facts suggest that pp135 is a signaling molecule that has a unique enzymatic activity and should play an important role in the signaling pathway triggered by GM-CSF and in the transformation of hematopoietic cells caused by Bcr-Abl.
 ...
PMID:Purification and molecular cloning of SH2- and SH3-containing inositol polyphosphate-5-phosphatase, which is involved in the signaling pathway of granulocyte-macrophage colony-stimulating factor, erythropoietin, and Bcr-Abl. 910 92

Crkl, a 39-kD SH2, SH3 domain-containing adapter protein, is constitutively tyrosine phosphorylated in hematopoietic cells from chronic myelogenous leukemia (CML) patients. We recently reported that thrombopoietin induces tyrosine phosphorylation of Crkl in normal platelets. In this study, we demonstrate that thrombopoietin induces association of Crkl with a tyrosine phosphorylated 95- to 100-kD protein in platelets and in UT7/TPO cells, a thrombopoietin-dependent megakaryocytic cell line. With specific antibodies against STAT5, we demonstrate that the 95- to 100-kD protein in Crkl immunoprecipitates is STAT5. This coimmunoprecipitation was specific in that Crkl immunoprecipitates do not contain STAT3, although STAT3 becomes tyrosine phosphorylated in thrombopoietin-stimulated platelets. The coimmunoprecipitaion of Crkl with STAT5 was inhibited by the immunizing peptide for Crkl antisera or phenyl phosphate (20 mmol/L). After denaturing of Crkl immunoprecipitates, Crkl was still immunoprecipitated by Crkl antisera. However, coimmunoprecipitation of STAT5 was not observed. Coincident with STAT5 tyrosine phosphorylation, thrombopoietin induces activation of STAT5 DNA-binding activity as demonstrated by electrophoretic mobility shift assays (EMSA). Using a beta-casein promoter STAT5 binding site as a probe, we have also demonstrated that Crkl antisera supershift the STAT5-DNA complex, suggesting that Crkl is a component of the complex in the nucleus. Furthermore, interleukin-3 (IL-3), granulocyte-macrophage colony-stimulating factor (GM-CSF), and erythropoietin also induce Crkl-STAT5 complex formation in responding cells in a stimulation-dependent manner. In vitro, glutathione S-transferase (GST)-Crkl bound to STAT5 inducibly through its SH2 domain. These results indicate that thrombopoietin, IL-3, GM-CSF, and erythropoietin commonly induce association of STAT5 and Crkl and that the complex translocates to the nucleus and binds to DNA. Interestingly, such association between STAT5 and Crkl was not observed in cytokine-stimulated murine cells, suggesting an intriguing possibility that components of the human STAT5-DNA complex may be different from those of the murine counterpart.
 ...
PMID:Thrombopoietin induces association of Crkl with STAT5 but not STAT3 in human platelets. 984 31

Our laboratory has been involved in the study of glutathione-sulfhydryl-transferase-pi (GST-pi) for several years. We have recently observed that during haematopoiesis in BMSC liquid cultures from CML patients who were candidates for transplant GST-pi was expressed in presumably malignant cells during different stages of cellular maturation. To confirm this finding, in the present work we are detecting GST-pi expression by immunofluorescence in BCR-ABL+ and BCR-ABL- cells done by FISH of PB from 30 CML patients during different clinical status: treatment (T), hematological relapse (R), blastic crisis (BC) or post-allotrasplant (PT). As well as in PB from 30 Blood-Bank donors. The results were %BCR-ABL+ GST-pi+ cells: T = 1-67, R = 33-69, BC = 90-100 and PT = 1-2; %BCR-ABL- GST-pi+ cells: T = 2-31, R = 5-18, BC = 0-10 and PT = 2-5; %BCR-ABL- GST-pi- cells: T = 2-97, R = 13-62, BC = 0 and PT = 93-96; %BCR-ABL+ GST-pi- cells: T = 0, R = 0, BC = 0 and PT = 0. GST-pi was not expressed in donor cells. The results obtained confirm our previous observations and suggest that GST-pi expression might be used for the evaluation of the minimal residual disease in CML patients.
 ...
PMID:GST-pi expression in BCR-ABL+ and BCR-ABL- cells from CML patients. 1095 10


1 2 3 Next >>