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)

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.
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PMID:Structure and regulation of Kit protein-tyrosine kinase--the stem cell factor receptor. 1622 10

Resistance to imatinib mesylate is an emerging problem in the treatment of chronic myeloid leukemia (CML), often associated with point mutations in the Bcr-Abl kinase domain. Outcome of patients with such mutations after allogeneic stem cell transplantation (Allo-SCT) is unknown. Ten imatinib-resistant patients with Bcr-Abl kinase mutations received a transplant: 9 had CML (3 in chronic phase, 4 in accelerated phase, and 2 in blast phase) and 1 had Philadelphia-positive acute lymphocytic leukemia (ALL). Patients harbored 9 different protein kinase mutations (T315I mutation, n = 2). Preparative regimens were ablative (n = 7) and nonablative (n = 3). All patients engrafted; there were no treatment-related deaths. Disease response was complete molecular (CMR; n = 7), major molecular (n = 2), and no response (n = 1). Three patients (mutations Q252H, E255K, and T315I) died of relapse after Allo-SCT. Seven patients are alive (6 in CMR) for a median of 19 months. Allo-SCT remains an important salvage option for patients who develop resistance to imatinib through Bcr-Abl mutations.
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PMID:Allogeneic stem cell transplantation for patients with chronic myeloid leukemia and acute lymphocytic leukemia after Bcr-Abl kinase mutation-related imatinib failure. 1660 Dec 47

Indirubin, an isomer of indigo, is a reported inhibitor of cyclin-dependent kinases (CDKs) and glycogen synthase kinase-3 (GSK-3) as well as an agonist of the aryl hydrocarbon receptor (AhR). Indirubin is the active ingredient of a traditional Chinese medicinal recipe used against chronic myelocytic leukemia. Numerous indirubin analogs have been synthesized to optimize this promising kinase inhibitor scaffold. We report here on the cellular effects of 7-bromoindirubin-3'-oxime (7BIO). In contrast to its 5-bromo- and 6-bromo- isomers, and to indirubin-3'-oxime, 7BIO has only a marginal inhibitory activity towards CDKs and GSK-3. Unexpectedly, 7BIO triggers a rapid cell death process distinct from apoptosis. 7-Bromoindirubin-3'-oxime induces the appearance of large pycnotic nuclei, without classical features of apoptosis such as chromatin condensation and nuclear fragmentation. 7-Bromoindirubin-3'-oxime-induced cell death is not accompanied by cytochrome c release neither by any measurable effector caspase activation. Furthermore, the death process is not altered either by the presence of Q-VD-OPh, a broad-spectrum caspase inhibitor, or the overexpression of Bcl-2 and Bcl-XL proteins. Neither AhR nor p53 is required during 7BIO-induced cell death. Thus, in contrast to previously described indirubins, 7BIO triggers the activation of non-apoptotic cell death, possibly through necroptosis or autophagy. Although their molecular targets remain to be identified, 7-substituted indirubins may constitute a new class of potential antitumor compounds that would retain their activity in cells refractory to apoptosis.
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PMID:7-Bromoindirubin-3'-oxime induces caspase-independent cell death. 1670 56

The Bcr-Abl tyrosine kinase is the causative factor in most chronic myelogenous leukemia (CML) patients. We have shown that Bcr-Abl is associated with a cluster of signaling proteins, including Janus kinase (Jak) 2, growth factor receptor binding protein 2-associated binder (Gab) 2, Akt, and glycogen synthase kinase (GSK)-3beta. Treatment of CML cell lines and mouse Bcr-Abl+ 32D cells with either Jak2 short interfering RNA or Jak2 kinase inhibitor AG490 inhibited pTyr Gab2 and pSer Akt formation, inhibited the activation of nuclear factor-kappaB, and caused the activation of GSK-3beta, leading to the reduction of c-Myc. Importantly, BaF3 cells expressing T315I and E255K imatinib-resistant mutants of Bcr-Abl underwent apoptosis on exposure to AG490 yet were resistant to imatinib. Similar to wild-type Bcr-Abl+ cells, inhibition of Jak2 by Ag490 treatment resulted in decrease of pSer Akt and c-Myc in imatinib-resistant cells. These results identify Jak2 as a potentially important therapeutic target for CML.
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PMID:Janus kinase 2: a critical target in chronic myelogenous leukemia. 1681 14

With the rapid development of high-throughput techniques for identifying novel specific molecular targets in human cancer over the past few years, attention to targeted cancer therapy has dramatically increased. The term "targeted cancer therapy" refers to a new generation of drugs designed to interfere with a specific molecular target that is believed to play a critical role in tumor growth or progression, is not expressed significantly in normal cells, and is correlated with clinical outcome. There has been a rapid increase in the identification of targets that have potential therapeutic application. The clinical success of the small-molecule kinase inhibitor imatinib mesylate in chronic myeloid leukemia and gastrointestinal stromal tumors has accelerated the development of a new era of molecular targeted cancer therapy. The number of agents under preclinical and clinical investigation has grown accordingly. This emphasis on molecular biology and genetics has also resulted in significant changes in the treatment of gynecologic cancers. Several promising drugs targeting tyrosine kinases (EGFR and Her-2/Neu), mTOR, Raf kinase, proteasome, and histone deacetylases, as well as drugs affecting apoptosis and mitosis, are under development for clinical application. However, some clinical trials of p53 gene therapies and farnesyl transferase inhibitors have had limited success. In this review, we will focus on potential novel targets in gynecologic cancer and the development of targeted therapy and its clinical applications in gynecologic cancer.
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PMID:Targeted therapies in gynecologic cancers. 1684 24

Acute myeloid leukaemia (AML) is the most common form of leukaemia in adults. Although of the order of 75-85% of patients will achieve complete remission after induction chemotherapy, long-term survival is still relatively low. Despite the progress in the rational design of drugs in disorders such as chronic myeloid leukaemia, AML lacks a single specific pathogenomic event to act as a drug target. Interferon regulatory factor 1 (IRF1) is a member of a family of related proteins that act as transcriptional activators or repressors. IRF1 and its functional antagonist IRF2 originally discovered as transcription factors regulating the interferon-beta (IFN-beta) gene, are involved in the regulation of normal haematopoiesis and leukaemogenesis. IRF1 appears to act as a tumour suppressor gene and IRF2 as an oncogene. IRF1 acts to repress IRF2 function through the repression of cyclin-dependent kinase (CDK) inhibitor p21WAF1 critical for cell growth control. It appears that the tumour suppression function of IRF1 is abolished by IRF2. This review focuses on the interaction between IRF1 and IRF2 in myeloid development and leukaemogenesis, particularly in relation to the Ras signalling pathway. IRF2 may be a viable and specific therapeutic target in human leukaemia.
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PMID:The role of IRF1 and IRF2 transcription factors in leukaemogenesis. 1707

SOCS-1, an important protein in the JAK/STAT pathway, has a role in the down stream of BCR-ABL protein kinase. We investigated 56 CML patients and 16 controls for the methylation status of SOCS-1 gene promoter and Exon 2 regions. Exon 2 was found to be methylated in 58.9% of the patients and 93.8% of the controls [P = 0.020, OR = 0.121(0.015-0.957)%95CI]. The promoter region was found unmethylated in all patient samples and controls. Although previous studies revealed a relation between SOCS1 gene Exon-2 hypermethylation and CML development or progression, the results of this study showed no such correlation. On the contrary, our results might be indicating hypomethylation in CML patients, this hypothesis need to be studied in larger study population.
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PMID:The SOCS-1 gene methylation in chronic myeloid leukemia patients. 1731 16

Deciphering the BCR-ABL-independent signaling exploited in chronic myeloid leukemia (CML) progression is an important aspect in cancer stem-cell biology. CML stem-cell compartment is dynamic as it progresses to terminal blast crisis where myeloid and lymphoid blasts fail to differentiate. We demonstrate cross-regulation of signaling network involving Sonic hedgehog (Shh), Wnt, Notch and Hox for the inexorable blastic transformation of CD34(+) CML cells. Significant upregulation in Patched1, Frizzled2, Lef1, CyclinD1, p21 (P < or =0.0002) and downregulation of HoxA10 and HoxB4 (P< or =0.0001) transcripts in CD34(+) cells distinguish blast crisis from chronic CML. We report Shh-dependent Stat3 activation orchestrates these mutually interconnected signaling pathways. Stimulation of CD34(+) CML cells with either soluble Shh or Wnt3a did not activate Akt or p44/42-mitogen activated protein kinase (MAPK) pathways. Interestingly, unlike dominant negative Stat3beta, introduction of constitutive active Stat3 in CD34(+) CML cells induces cross-regulation in gene expression. Additionally, Shh and Wnt3a-dependent regulation of cyclin-dependent kinase inhibitors (CDKI) in CML suggests their role in the network. Taken together, our findings propose that deregulation in the form of hyperactive Shh and Wnt with repressed Notch and Hox pathways involving Stat3, Gli3, beta-catenin, CyclinD1, Hes1, HoxA10 and p21 might act synergistically to form an important hub in CML progression.
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PMID:Deregulation and cross talk among Sonic hedgehog, Wnt, Hox and Notch signaling in chronic myeloid leukemia progression. 1736 Dec 18

The search for specific protein kinase inhibitors is an intense area of research because of the potential for drug development. The small-molecule inhibitor imatinib (Gleevec/STI-571) can specifically inactivate the tyrosine kinase c-Abl, whose normal mechanism of autoinhibition is disrupted in chronic myelogenous leukemia. Crystallographic analysis of c-Abl reveals that imatinib recognizes a distinct inactive conformation of the Abl kinase domain that relies on the mechanism of autoinhibition achieved in the context of a larger fragment of the protein. This mechanism is distinct from that seen in the related Src family kinases, where autoinhibition is achieved through the internal engagement of a C-terminal phosphotyrosine residue by the Src homology 2 domain (SH2) domain. Notably, this phosphotyrosine residue is lacking in c-Abl, where instead autoinhibition is mediated by an interaction between the kinase domain and the N-terminal myristoyl modification. Within the framework of these 2 distinct modes of autoinhibition, the SH3-SH2 unit is structurally conserved between Abl and Src, leading to large conformational differences in their kinase domains. These differences help explain the ability of imatinib to preferentially inhibit Abl over Src.
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PMID:c-Abl tyrosine kinase and inhibition by the cancer drug imatinib (Gleevec/STI-571). 1751 18

This article reviews several important observations in the field of protein kinase drug discovery, exemplified mainly by targeting c-Abl for the treatment of CML. Structure-based strategy and insight are provided for the optimization of the selectivity and resistant mutation profiles of protein kinase inhibitors.
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PMID:Molecular targeting of protein kinases to optimize selectivity and resistance profiles of kinase inhibitors. 1769 23


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