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)

Bcr-Abl, the product of the protooncogene bcr-abl, is a constitutively active protein-tyrosine kinase that is highly expressed in chronic myelogenous leukemia and in acute myeloid leukemia cells. Because Bcr-Abl is known to provide mitogenic signals through suppression of apoptosis, we investigated the effect of this oncogene product on signaling by tumor necrosis factor (TNF), a proapoptotic cytokine. We used a bcr-abl-deficient human megakaryocytic leukemia cell line MO7E and an isogenic MBA cell line stably transfected with bcr-abl. Electrophoretic mobility shift assay revealed that TNF activated the nuclear transcription factor NF-kappaB in MO7E cells but not in MBA cells. The impaired NF-kappaB activation in Bcr-Abl-expressing cells was not due to absence of the NF-kappaB proteins p65, p50, or p100 or of IkappaBalpha or IkappaBbeta. Okadaic acid-induced NF-kappaB activation was unaffected by Bcr-Abl expression. TNF induced IkappaBalpha phosphorylation and degradation in MO7E cells but not in MBA cells. The suppression of TNF-induced NF-kappaB activation by Bcr-Abl was not restricted to MBA cells, because ectopic expression of Bcr-Abl in human acute myeloid leukemia HL-60 cells also blocked TNF-induced NF-kappaB activation. When examined for the TNF receptors by the radioreceptor assay, flow cytometry, or Western blot analysis, we found that Bcr-Abl expression down-regulated the expression of the TNF receptors. The RNase protection assay and Northern blot analysis revealed the transcriptional down-regulation of the TNF receptor by Bcr-Abl protein. Overall, these results indicate that ectopic expression of Bcr-Abl interferes with the TNF signaling pathway through the down-regulation of TNF receptors.
 ...
PMID:Ectopic expression of protein-tyrosine kinase Bcr-Abl suppresses tumor necrosis factor (TNF)-induced NF-kappa B activation and IkappaBalpha phosphorylation. Relationship with down-regulation of TNF receptors. 1206 Jun 65

Imatinib mesilate (Glivec) is a protein-tyrosine kinase inhibitor that potently inhibits the Bcr-Abl tyrosine kinase as well as the receptors for platelet-derived growth factor (PDGF) and stem cell factor (SCF), c-Kit, at in vitro and cellular kinase assay levels. Since Bcr-Abl tyrosine kinase plays a key role in chronic myelogenous leukemia (CML) patients, treatment with imatinib mesilate that potently inhibits Bcr-Abl tyrosine kinase could be a promising therapeutic approach to CML. Imatinib mesilate was shown to inhibit proliferation of bcr-abl-positive cell lines and suppress the formation of bcr-abl-positive colonies in cells derived from bone marrow of CML patients. This compound induced apoptosis in a variety of bcr-abl-positive cells. Moreover, in vivo data indicated that imatinib mesilate suppress growth and formation of bcr-abl-positive tumors in mice. As the profile expected from the preclinical studies, imatinib mesilate showed impressive hematological and cytogenic responses in the clinical trials, including interferon-alpha-resistant or intolerant patients.
 ...
PMID:[Preclinical and clinical profile of imatinib mesilate, a potent protein-tyrosine kinase inhibitor for CML therapy]. 1261 57

The Bcr-Abl protein-tyrosine kinase is implicated in the development of chronic myeloid leukemia. The potential role of protein-tyrosine phosphatase in the regulation of Bcr-Abl signaling was explored. First, expression patterns of tyrosine phosphatases in leukemic cell lines were investigated using degenerate primers for reverse transcription-PCR followed by cloning and sequencing of the cDNA. Distinct patterns of distribution of phosphatase were found in erythroid and myeloid leukemic cell lines. Whereas some phosphatases were ubiquitously expressed, others were limited to specific cell types. Surprisingly, a previously cloned "lymphocyte-specific" phosphatase, Lyp, was frequently detected in a number of myeloid cell lines as well as normal granulocytes and monocytes. Lyp was localized to the cytosol, and overexpression of Lyp caused reduction in the phosphorylation levels of multiple proteins in KCL22 chronic myeloid leukemia blast cells including Cbl, Bcr-Abl, Erk1/2, and CrkL. Co-expression of Lyp and Bcr-Abl in Cos-7 cells resulted in decreased levels of Bcr-Abl, Grb2, and Myc. Overexpression of Lyp markedly suppressed anchorage-independent clonal growth of KCL22 cells. Taken together, the data suggest that Lyp may play an antagonistic role in signaling by the Bcr-Abl fusion protein.
 ...
PMID:Characterization of a myeloid tyrosine phosphatase, Lyp, and its role in the Bcr-Abl signal transduction pathway. 1276 53

STI-571 (imatinib, Gleevec, Glivec, CGP 57148) is an inhibitor of the Abl group of protein-tyrosine kinases. One of these enzymes, the Bcr-Abl oncoprotein, results from the fusion of the BCR and ABL genes that result from the reciprocal chromosomal translocation that forms the Philadelphia chromosome. The Philadelphia chromosome occurs in 95% of people with chronic myeloid leukemia. ABL is the cellular homologue of the oncogene found in murine Abelson leukemia virus, and BCR refers to breakpoint cluster region. The Bcr-Abl oncoprotein exhibits elevated protein-tyrosine kinase activity, which is strongly implicated in the mechanism of development of chronic myeloid leukemia. STI-571 is effective in the treatment of the stable phase of chronic myeloid leukemia. The c-Abl protein kinase domain exists in an active and inactive conformation. STI-571 binds only to the inactive state of the enzyme as shown by X-ray crystallography. The drug binds to a portion of the ATP-binding site and extends from there into adjacent hydrophobic regions. STI-571 is a competitive inhibitor of Abl kinase with respect to ATP. Resistance to STI-571 is often the result of mutations in residues of the Bcr-Abl kinase that ordinarily bind to the drug. Inhibition of target protein kinases represents an emerging therapeutic strategy for the treatment of cancer.
 ...
PMID:STI-571: an anticancer protein-tyrosine kinase inhibitor. 1367 30

Hypereosinophilic syndrome (HES) is a heterogeneous group of rare disorders characterized by peripheral blood and tissue eosinophilia leading to end-organ damage. Hypereosinophilic syndrome can be fatal, particularly in patients with endomyocardial fibrosis, and treatment has traditionally been palliative or preventive. The disease shares features with myeloproliferative disorders, such as chronic myeloid leukemia, including responsiveness to hydroxyurea and interferon. The tyrosine kinase inhibitor imatinib, a highly effective treatment for chronic myeloid leukemia, has shown efficacy in normalizing eosinophil counts and resolving signs and symptoms in some HES patients. Fusion of the Fip1-like 1 gene (FIP1L1) and the platelet-derived growth factor receptor alpha gene (PDGFRA) was discovered in the majority of patients with imatinib-sensitive HES, and all patients with the fusion responded to imatinib. The product of this fusion gene, FIP1L1-PDGFRalpha, is a constitutively active protein-tyrosine kinase capable of transforming hematopoietic cells. The efficacy of relatively low imatinib concentrations in HES, mediated by inhibition of FIP1L1-PDGFRalpha kinase activity, causally implicates FIP1L1-PDGFRA in the pathogenesis in certain HES patients.
 ...
PMID:Platelet-derived growth factor receptor inhibition to treat idiopathic hypereosinophilic syndrome. 1517 99

Increasing knowledge of the mechanism of the initiation and progression of various cancers is the catalyst for developing new anticancer therapeutics that target specific molecules expressed in cancer cells. STI571 (imatinib mesylate) is an example of the successful development of a rationally designed and targeted agent. Its target is the constitutively active tyrosine kinase, BCR-ABL in chronic myelogenous leukemia (CML). Clinical studies with STI571 in CML demonstrated that many patients with advanced stage disease respond initially but then relapse. Drug resistance is associated with the reactivation of BCR-ABL signal transduction. Another targeted protein-tyrosine kinase inhibitor that was approved for clinical use is ZD1839 (Iressa). ZD1839 is an orally active and selective inhibitor for epidermal growth factor receptor (EGFR) tyrosine kinase. HER2 is overexpressed in 25-30% of breast cancers and associated with shorter time to relapse and lower survival rate. Specific targeting of these cancers can be accomplished with Herceptin directed against the extracellular domain of the HER2 protein. However, even in the selected group of patients with high levels of HER2, the response to Herceptin is limited in magnitude and duration. The mechanisms of the resistance to these targeted agents were reviewed.
 ...
PMID:[The mechanisms of the resistance to molecular targeting agents]. 1528 47

The cellular fes gene encodes a 93-kilodalton protein-tyrosine kinase (p93) that is expressed in both normal and neoplastic myeloid cells. Increased c-Fes expression is associated with differentiation in normal myeloid cells and cell lines. Our hypothesis was that primary leukemia cells would show a similar pattern of increased expression in more differentiated cells. Therefore, we compared c-Fes expression in cells with an undifferentiated, blast phenotype (acute myelogenous leukemia--AML) to cells with a differentiated phenotype (chronic myelogenous leukemia--CML). Instead of differences in p93 expression levels, we found complex patterns of c-Fes immunoreactive proteins that corresponded with differentiation in normal and leukemic myeloid cells. The "blast" pattern consisted of c-Fes immunoreactive proteins p93, p74, and p70; the "differentiated" pattern showed two additional c-Fes immunoreactive proteins, p67 and p62. Using mRNA from mouse and human cell lines, we found deletion of one or more exons in the c-fes mRNA. Those deletions predicted truncation of conserved domains (CDC15/FCH and SH2) involved in protein-protein interactions. No deletions were found, however, within the kinase domain. We infer that alternative splicing generates a family of c-Fes proteins. This may be a mechanism to direct the c-Fes kinase domain to different subcellular locations and/or substrates at specific stages of myeloid cell differentiation.
 ...
PMID:Expression of c-Fes protein isoforms correlates with differentiation in myeloid leukemias. 1586 8

Signaling by stem cell factor and Kit, its receptor, play important roles in gametogenesis, hematopoiesis, mast cell development and function, and melanogenesis. Moreover, human and mouse embryonic stem cells express Kit transcripts. Stem cell factor exists as both a soluble and a membrane-bound glycoprotein while Kit is a glycoprotein receptor protein-tyrosine kinase. The complete absence of stem cell factor or Kit is lethal. Gain-of-function mutations of Kit are associated with several human neoplasms including acute myelogenous leukemia, gastrointestinal stromal tumors, mastocytomas, and nasal T-cell lymphomas. Binding of stem cell factor to Kit results in receptor dimerization and activation of protein kinase activity. The activated receptor becomes autophosphorylated at tyrosine residues that serve as docking sites for signal transduction molecules containing SH2 domains. Kit activates Akt, Src family kinases, phosphatidylinositol 3-kinase, phospholipase Cgamma, and Ras/mitogen-activated protein kinases. Kit exists in active and inactive conformations as determined by X-ray crystallography. Kit consists of an extracellular domain, a transmembrane segment, a juxtamembrane domain, and a protein kinase domain that contains an insert of about 80 amino acid residues. The juxtamembrane domain inhibits enzyme activity in cis by maintaining the control alphaC-helix and the activation loop in their inactive conformations. The juxtamembrane domain also inhibits receptor dimerization. STI-571, a clinically effective targeted protein-tyrosine kinase inhibitor, binds to an inactive conformation of Kit. The majority of human gastrointestinal stromal tumors have Kit gain-of-function mutations in the juxtamembrane domain, and most people with these tumors respond to STI-571. STI-571 binds to Kit and Bcr-Abl (the oncoprotein of chronic myelogenous leukemia) at their ATP-binding sites.
 ...
PMID:Structure and regulation of Kit protein-tyrosine kinase--the stem cell factor receptor. 1622 10

Bcr-Abl is the oncogenic protein-tyrosine kinase responsible for chronic myelogenous leukemia. Recently, we observed that inhibition of myeloid Src family kinase activity (e.g. Hck, Lyn, and Fyn) induces growth arrest and apoptosis in Bcr-Abl-transformed cells, suggesting that cell transformation by Bcr-Abl involves Src family kinases (Wilson, M. B., Schreiner, S. J., Choi, H. J., Kamens, J., and Smithgall, T. E. (2002) Oncogene 21, 8075-8088). Here, we report the unexpected observation that Hck, Lyn, and Fyn strongly phosphorylate the SH3-SH2 region of Bcr-Abl. Seven phosphorylation sites were identified by matrix-assisted laser desorption ionization time-of-flight mass spectrometry: Tyr89 and Tyr134 in the Abl-derived SH3 domain; Tyr147 in the SH3-SH2 connector; and Tyr158, Tyr191, Tyr204, and Tyr234 in the SH2 domain. SH3 domain Tyr89, the most prominent phosphorylation site in vitro, was strongly phosphorylated in chronic myelogenous leukemia cells in a Src family kinase-dependent manner. Substitution of the SH3-SH2 tyrosine phosphorylation sites with phenylalanine substantially reduced Bcr-Abl-mediated transformation of TF-1 myeloid cells to cytokine independence. The positions of these tyrosines in the crystal structure of the c-Abl core and the transformation defect of the corresponding Bcr-Abl mutants together suggest that phosphorylation of the SH3-SH2 region by Src family kinases impacts Bcr-Abl protein conformation and signaling.
 ...
PMID:Src family kinases phosphorylate the Bcr-Abl SH3-SH2 region and modulate Bcr-Abl transforming activity. 1691 36

Imatinib is one of the most recent medications used for the treatment of chronic myeloid leukemia (CML) and gastrointestinal stromal tumor (GIST). It is an orally administered protein-tyrosine kinase inhibitor, an enzyme which is produced by BCR-ABL fusion which results from translocation of 9:22 chromosome (Philadelphia chromosome). Imatinib blocks proliferation and induces apoptosis of BCR-ABL-expression in CML. Many side effects produced by imatinib have been documented but its induction of hepatotoxcity has been rarely reported. Only a few cases so far have been reported in the literature and almost all were in females. We describe another case of hepatotoxicity due to imatinib in a 17-year old female with clinical, laboratory and histopathological changes. The case described here suggests that imatinib may also induce immune hepatitis, in some patients.
 ...
PMID:Imatinib-induced immune hepatitis: case report and literature review. 1736 93


<< Previous 1 2 3 Next >>