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 BCR protein is involved in the inhibition of oncogenic activity of the Bcr-Abl oncoprotein. This inhibition is believed to be the result of binding to the SH2 domain of Bcr-Abl in a non-phosphotyrosine-dependent manner. We showed that the Arg to Leu mutation in the Phe-Leu-Val-Arg-Glu-Ser (FLVRES) sequence of the SH2 domain, known to interfere with phosphotyrosine sequence binding, did not block the binding of Bcr first exon sequences to the Abl SH2 domain. We examined the structural-functional properties of a first exon mutant of BCR lacking the oligomerization domain, termed Bcr(64-413), that encodes the Ser-Thr protein kinase activity of Bcr. The autokinase product contained a M(r) 45,000-47,000 and 55,000 protein. Both species were detected by a Bcr phosphoserine 354 sequence-specific antibody. In contrast, the S354A mutant of Bcr(64-413), although maintaining autokinase activity, produced only the M(r) 45,000-47,000 kinase product. Abl SH2 binding experiments indicated that the M(r) 55,000 species of Bcr(64-413) but not the M(r) 45,000-47,000 species bound strongly to glutathime transferase-Abl SH2. The S354A mutant of Bcr(64-413) did not bind to glutathime transferase-Abl SH2. An adenovirus encoding Bcr(64-413) S354A did not induce cell death in CML cell lines in contrast to wild-type Bcr(64-413). Our findings indicate that Ser-354 of Bcr is part of a gating mechanism, which, after its phosphorylation, allows structural changes to occur in the Bcr protein. This altered phosphoserine form of the Bcr protein selectively binds to the Abl SH2 domain of the oncoprotein, which we propose down-regulates the activity of the Bcr-Abl tyrosine kinase.
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PMID:Inhibition of the Bcr-Abl oncoprotein by Bcr requires phosphoserine 354. 1180 85

STI571, a selective inhibitor of Bcr-Abl, has been a successful therapeutic agent in clinical trials for chronic myelogenous leukemia. Chronic phase chronic myelogenous leukemia patients treated with STI571 have durable responses; however, most responding blast phase patients relapse despite continued therapy. Co-crystallization studies of Abl kinase and an STI571-related compound identify specific amino acid residues as critical to STI571 binding, one of which, T315, has been characterized as an acquired Thr to Ile mutation in relapsed patients. Other studies, however, suggest that mutations other than these predicted contact points are capable of conferring STI571 resistance in relapsed patients. Using a variety of models of STI571 binding to the Abl kinase, we have performed an extensive mutational analysis of sites that might alter the sensitivity of the Abl kinase to STI571. Although mutation of many of the predicted contact points between Abl and STI571 result in a kinase-inactive protein, additional mutations that render the Abl kinase less sensitive to STI571 demonstrate a broad range of possibilities for clinical resistance that are now becoming evident.
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PMID:Analysis of the structural basis of specificity of inhibition of the Abl kinase by STI571. 1207 14

The Abl tyrosine kinase inhibitor STI-571 is effective therapy for stable phase chronic myeloid leukemia (CML) patients, but the majority of CML blast-crisis patients that respond to STI-571 relapse because of reactivation of Bcr-Abl signaling. Mutations of Thr-315 in the Abl kinase domain to Ile (T315I) were previously described in STI-571-resistant patients and likely cause resistance from steric interference with drug binding. Here we identify mutations of Tyr-253 in the nucleotide-binding (P) loop of the Abl kinase domain to Phe or His in patients with advanced CML and acquired STI-571 resistance. Bcr-Abl Y253F demonstrated intermediate resistance to STI-571 in vitro and in vivo when compared with Bcr-Abl T315I. The response of Abl proteins to STI-571 was influenced by the regulatory state of the kinase and by tyrosine phosphorylation. The sensitivity of purified c-Abl to STI-571 was increased by a dysregulating mutation (P112L) in the Src homology 3 domain of Abl but decreased by phosphorylation at the regulatory Tyr-393. In contrast, the Y253F mutation dysregulated c-Abl and conferred intrinsic but not absolute resistance to STI-571 that was independent of Tyr-393 phosphorylation. The Abl P-loop is a second target for mutations that confer resistance to STI-571 in advanced CML, and the Y253F mutation may impair the induced-fit interaction of STI-571 with the Abl catalytic domain rather than sterically blocking binding of the drug. Because clinical resistance induced by the Y253F mutation might be overcome by dose escalation of STI-571, molecular genotyping of STI-571-resistant patients may provide information useful for rational therapeutic management.
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PMID:Clinical resistance to the kinase inhibitor STI-571 in chronic myeloid leukemia by mutation of Tyr-253 in the Abl kinase domain P-loop. 1214 56

Small molecule inhibitors of protein tyrosine kinases such as STI571 represent a major new class of therapeutics for target-selective treatment of human cancer. Clinical resistance formation to the BCR-ABL inhibitor STI571 has been observed in patients with advanced chronic myeloid leukemia and was frequently caused by a C to T single nucleotide change in the Abl kinase domain, which substituted Thr-315 with isoleucine and rendered BCR-ABL resistant to STI571 inhibition. The corresponding mutation in the epidermal growth factor receptor (EGFR) tyrosine kinase replaced Thr-766 of the EGFR by methionine and dramatically reduced the sensitivity of EGFR to inhibition by selective 4-anilinoquinazoline inhibitors such as PD153035. Inhibitor-resistant EGFR exhibited the same signaling capacity as wild-type receptor in vivo and provides a useful tool for analyzing EGFR-mediated signal transduction. Our data identify Thr-766 of the EGFR as a structural determinant that bears the potential to become a relevant feature in resistance formation during cancer therapy with EGFR-specific 4-anilinoquinazoline inhibitors.
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PMID:Mutation of threonine 766 in the epidermal growth factor receptor reveals a hotspot for resistance formation against selective tyrosine kinase inhibitors. 1259 13

Imatinib (Gleevec) (formerly STI571) has been shown to selectively inhibit the tyrosine kinase domain of the oncogenic BCR-ABL fusion protein of chronic myelogenous leukemia (CML) cells. In recent phase I and II studies testing this new compound in patients who had failed to respond to interferon (IFN), hematological and cytogenetic responses were reported in most of those with chronic-phase CML. However, in some patients resistance has been associated with a single amino acid substitution in a threonine residue of the Abl kinase domain. In vitro studies examining the effects of imatinib plus cytarabine (Ara-C) using CML cell lines and colony-forming assays of CML patient samples have shown synergistic antiproliferative effects of this combination. Thus several groups decided to investigate this new combination with the hypothesis that cell resistance would be less frequent. The CML French Group performed a phase II trial to determine the safety and tolerability of a combination of imatinib and Ara-C for previously untreated patients with chronic-phase CML. Treatment was administered on 28-day cycles for 12 months. Patients were treated continuously with imatinib orally at a dose of 400 mg daily. Ara-C was given on days 14 to 28 of each cycle at an initial dose of 20 mg/m(2)/d via subcutaneous injection, hydroxyurea (HU) being stopped at least 7 days before imatinib. Recently, the Dutch group decided to explore a combination of high-dose Ara-C with imatinib in patients in chronic-phase CML. Preliminary results are encouraging. However, a long follow-up is required before concluding that these strategies will overcome cell resistance.
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PMID:Imatinib in combination with cytarabine for the treatment of Philadelphia-positive chronic myelogenous leukemia chronic-phase patients: rationale and design of phase I/II trials. 1278 82

The chimeric bcr-abl tyrosine kinase is of crucial pathogenic importance in chronic myeloid leukemia (CML). As shown, bcr-abl activates the ras pathway by phosphorylation of adapter proteins such as Grb-2 and Crkl. Functional inhibition of p21ras might partially inhibit the mitogenic signaling by bcr-abl. By depletion of cellular mevalonate pools, p21ras proteins can be rendered non-functional as a result of deficient post-translational protein farnesylation. We investigated the pharmacologic effect of mevalonate depletion by lovastatin in conjunction with interferon-alpha 2b (INF-alpha 2b) in bcr-abl positive K562 cells. At various concentrations, both drugs synergistically reduced cell proliferation of CML line K562 in a liquid culture system as well as clonal growth of colony forming units in a patient with newly diagnosed CML. Lovastatin and IFN-alpha 2b in combination led to cell cycle arrest and resulted in significant reduction of phosphorylation on tyrosine, serine, and threonine protein residues. IFN-alpha 2b alone showed little effect on protein phosphorylation but strongly enhanced lovastatin driven loss of phosphorylation. Subsequently, DNA fragmentation occurred in 50% of cells. In conclusion, exposure to IFN-alpha 2b and lovastatin synergistically inhibited proliferation of bcr-abl positive cells and resulted in loss of protein phosphorylation and subsequent apoptosis in K562 cells. Our in vitro model suggests further investigations are required of the potential value of HMG-CoA reductase inhibitors as adjunct to therapy of CML with interferon.
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PMID:Synergistic growth inhibitory effects of interferon-alpha and lovastatin on bcr-abl positive leukemic cells. 1279 88

Most of the signal transduction pathways are mediated by protein kinases regulating every aspect of cell function. Mutations which deregulate their expression or their function or both result in cancers. Therefore, protein kinase inhibitors has become the focus of development of new therapies for cancer. Almost all 120 protein tyrosine kinases are involved in signaling, whereas only a handful of Ser/Thr kinases are involved. Thus, most of the effort is directed toward the development of tyrosine phosphorylation inhibitors. The success of Gleevec in the treatment of chronic myeloid leukemia and of Iressa for lung cancer validates the approach.
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PMID:Protein kinase inhibitors as a therapeutic modality. 1280 33

Identification of signaling pathways downstream of Abl tyrosine kinase may increase our understanding of the pathogenesis of chronic myelogenous leukemia (CML) and suggest strategies to improve clinical treatment of the disease. By combining the use of a phosphospecific antibody recognizing a substrate motif of serine/threonine kinases with bioinformatics, we found that the translational regulators ribosomal protein S6 and 4E-BP1 are constitutively phosphorylated in CML cells. Experiments with specific inhibitors indicated the phosphorylation is downstream of Bcr-Abl kinase and the mammalian target of rapamycin (mTOR). These results suggest that Bcr-Abl may regulate translation of critical targets in CML cells via mTOR. They also provide a rationale for testing the combination of mTOR inhibitors with the Abl kinase inhibitor imatinib in patients with CML. The mTOR inhibitor rapamycin enhanced imatinib-mediated killing of CML cell lines in vitro, and it overcame imatinib resistance in cells with Bcr-Abl gene amplification.
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PMID:Bcr-Abl kinase modulates the translation regulators ribosomal protein S6 and 4E-BP1 in chronic myelogenous leukemia cells via the mammalian target of rapamycin. 1452 90

The protein kinase C (PKC) family of serine/threonine kinases plays an important role in numerous cancer signaling pathways, including those downstream of the bcr-abl oncogene. We demonstrated previously that atypical PKCiota is required for Bcr-Abl-mediated resistance of human K562 chronic myelogenous leukemia (CML) cells to Taxol-induced apoptosis. Here, we report that the pattern of PKC isozyme expression characteristic of CML cells is regulated by Bcr-Abl. When Bcr-Abl was expressed in Bcr-Abl-negative HL-60 promyelocytic leukemia cells, expression of the PKCbetaI, PKCbetaII, and PKCiota genes was induced, whereas expression of the PKCdelta gene was reduced to levels similar to those found in CML cells. Given the importance of PKCiota in Bcr-Abl-mediated transformation, we characterized the mechanism by which Bcr-Abl regulates PKCiota expression. A 1200-bp PKCiota promoter construct isolated from genomic DNA was highly active in Bcr-Abl-positive K562 cells and was activated when Bcr-Abl-negative cells were transfected with Bcr-Abl. Bcr-Abl-mediated induction of the PKCiota promoter was dependent upon MEK1/2 activity, but not phosphatidylinositol 3-kinase or p38 MAPK activity. Mutational analysis of the PKCiota promoter revealed a region between 97 and 114 bp upstream of the transcriptional start site that is responsible for Bcr-Abl-mediated regulation. Mutation of a consensus Elk1-binding site within this region abolished Bcr-Abl-mediated regulation. We conclude that Bcr-Abl regulates PKCiota expression through the MEK-dependent activation of an Elk1 element within the proximal PKCiota promoter. Our results indicate that Bcr-Abl-mediated transformation involves transcriptional activation of the PKCiota gene, which in turn is required for Bcr-Abl-mediated chemoresistance.
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PMID:Bcr-Abl regulates protein kinase Ciota (PKCiota) transcription via an Elk1 site in the PKCiota promoter. 1467 Sep 60

Small molecule inhibitors belonging to the pyrido[2,3-d]pyrimidine class of compounds were developed as antagonists of protein tyrosine kinases implicated in cancer progression. Derivatives from this compound class are effective against most of the imatinib mesylate-resistant BCR-ABL mutants isolated from advanced chronic myeloid leukemia patients. Here, we established an efficient proteomics method employing an immobilized pyrido[2,3-d]pyrimidine ligand as an affinity probe and identified more than 30 human protein kinases affected by this class of compounds. Remarkably, in vitro kinase assays revealed that the serine/threonine kinases Rip-like interacting caspase-like apoptosis-regulatory protein kinase (RICK) and p38alpha were among the most potently inhibited kinase targets. Thus, pyrido[2,3-d]pyrimidines did not discriminate between tyrosine and serine/threonine kinases. Instead, we found that these inhibitors are quite selective for protein kinases possessing a conserved small amino acid residue such as threonine at a critical site of the ATP binding pocket. We further demonstrated inhibition of both p38 and RICK kinase activities in intact cells upon pyrido[2,3-d]pyrimidine inhibitor treatment. Moreover, the established functions of these two kinases as signal transducers of inflammatory responses could be correlated with a potent in vivo inhibition of cytokine production by a pyrido[2,3-d]pyrimidine compound. Thus, our data demonstrate the utility of proteomic methods employing immobilized kinase inhibitors for identifying new targets linked to previously unrecognized therapeutic applications.
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PMID:Chemical proteomic analysis reveals alternative modes of action for pyrido[2,3-d]pyrimidine kinase inhibitors. 1547 68


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