Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.1 (protein kinase)
 81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

Chronic myeloid leukaemia (CML) is an unusual malignancy in which myeloid progenitor cells are transformed by a single chromosomal translocation where the Bcr domain of chromosome 22 is placed adjacent to the proto-oncogene c-Abl of chromosome 9, resulting in constitutive Abl tyrosine kinase activity. This has a twofold effect: it causes increased numbers of myeloid progenitor cells and circulating myeloid cells, and it causes leakage of reactive oxygen species from mitochondria. We describe a kinetic and pharmacodynamic (PD) model of Bcr-Abl signalling in myeloid cells that is used to simulate effects of four classes of drugs: Bcr-Abl signalling inhibitors, such as imatinib, cyclin-dependent kinase inhibitors, and pro- and anti-oxidants. The model also has the potential to describe the PD effects of agents acting on other sites in the Bcr-Abl signalling pathway. Having calibrated the model against dose-response curves of these drugs acting as single agents on Bcr-Abl-transformed cells in vitro, the model was used to predict effects of the agents in combination. Used in conjunction with pharmacokinetic models, our PD model enables an approach to protocol optimization: large numbers of doses and timings and (in the case of combination treatments) relative dose ratios can be simulated in silico. Predicted selectivity, as well as efficacy, can be extracted from the model. An understanding of the Bcr-Abl signalling pathway has implications for strategies to prevent acquired drug resistance, and for preventing or delaying CML progression to its blast phase.
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PMID:A pharmacodynamic model of Bcr-Abl signalling in chronic myeloid leukaemia. 2510 70