Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Protein kinases have emerged as one of the most promising targets for rational drug discovery. In a similar manner to imatinib mesylate (Gleevec), hematological malignancies offer multiple pharmacologic opportunities for manipulation of kinase-induced tumor cell proliferation. Certain kinases have been validated as targets for drug discovery in hematological malignancies (such as BCR-ABL and FLT3); other novel kinases hold considerable interest for targeted intervention: myeloid leukemias (KDR, KIT, CSF-1R, RAS and RAF), lymphoid leukemias (JAK2 fusion protein, TIE-1, CDK modulators), lymphoma (ALK, CDK modulators, mTOR), myeloproliferative disorders (PDGF-R or FGF-R fusion gene products, FGF-R1) and myeloma (FGF-R3, STAT3). Over the past five years, the number of kinase-targeted drug therapies undergoing clinical development has increased exponentially. This review will focus on novel kinase targets currently undergoing preclinical and clinical investigation.
Curr Mol Med 2005 Nov
PMID:Kinases as drug discovery targets in hematologic malignancies. 1630 89

Septins are evolutionarily conserved GTP-binding proteins that can heteropolymerize into filaments. Recent studies have revealed that septins are involved in not only diverse normal cellular processes but also the pathogenesis of various diseases, including cancer. SEPT6 is ubiquitously expressed in tissues and one of the fusion partner genes of MLL in the 11q23 translocations implicated in acute leukemia. However, the roles of this septin in vivo remain elusive. We have developed Sept6-deficient mice that exhibited neither gross abnormalities, changes in cytokinesis, nor spontaneous malignancy. Sept6 deficiency did not cause any quantitative changes in any of the septins evaluated in this study, nor did it cause any additional changes in the Sept4-deficient mice. Even the depletion of Sept11, a close homolog of Sept6, did not affect the Sept6-null cells in vitro, thus implying a high degree of redundancy in the septin system. Furthermore, a loss of Sept6 did not alter the phenotype of myeloproliferative disease induced by MLL-SEPT6, thus suggesting that Sept6 does not function as a tumor suppressor. To our knowledge, this is the first report demonstrating that a disruption of the translocation partner gene of MLL in 11q23 translocation does not contribute to leukemogenesis by the MLL fusion gene.
Mol Cell Biol 2005 Dec
PMID:Disruption of Sept6, a fusion partner gene of MLL, does not affect ontogeny, leukemogenesis induced by MLL-SEPT6, or phenotype induced by the loss of Sept4. 1631 19

A single acquired mutation in the JAK2 gene has recently been described in human myeloproliferative disorders, including most patients with polycythemia vera and about half of those with essential thrombocythemia and idiopathic myelofibrosis. Reliable and easily implemented methods for detection of this V617F mutation promise to revolutionize the way these disorders are diagnosed and classified, and may in the future have implications for targeted therapeutics. Two polymerase chain reaction-based methods for detection of the mutation are described here. One method is based on allele-specific amplification of the mutant band, and the other on elimination of a restriction enzyme recognition sequence by the mutation. Both methods are significantly more sensitive than conventional sequencing techniques, and could be readily implemented in a molecular diagnostic laboratory.
Methods Mol Med 2006
PMID:Methods for the detection of the JAK2 V617F mutation in human myeloproliferative disorders. 1650 90

The polycythemia rubra vera 1 gene (PRV-1), a member of the urokinase-type plasminogen activator receptor superfamily, is overexpressed in granulocytes isolated from the peripheral blood of patients with polycythemia vera (PV) and essential thrombocythemia (ET). PRV-1 overexpression is the first reliable molecular marker of these myeloproliferative disorders, and its detection allows us to discriminate PV and ET from secondary erythrocytosis and thrombocytosis. PRV-1 overexpression can be investigated by several techniques, including Northern analysis, reverse-transcription (RT)-polymerase chain reaction (PCR), and real-time PCR. Among these, RT-PCR is the most rapid, reliable, and feasible method for the detection of PRV-1 overexpression in highly purified peripheral blood granulocytes.
Methods Mol Med 2006
PMID:Overexpression of PRV-1 gene in polycythemia rubra vera and essential thrombocythemia. 1650 91

Chronic myelogenous leukemia (CML) is a clonal myeloproliferative disorder that is characterized by the presence of a reciprocal translocation between chromosomes 9 and 22 and results in the formation of the Philadelphia (Ph1) chromosome and is present in most of CML patients. The Ph1 chromosome forms a chimeric gene that encodes an abnormal P210 mRNA transcript in most CML patients. Surveillance for minimal residual disease by detection of BCR/ABL transcripts is currently done mostly by quantitative real-time reverse transcriptase polymerase chain reaction (RT-PCR). Quantitation of BCR/ABL transcripts can monitor tumor load and the outcome of therapy. Absolute quantification determines the input copy number of the transcript of interest, usually by plotting the amount of PCR product onto a standard curve based on serial dilutions of the same product cloned in plasmids. Relative quantification describes the change in expression of the target gene in the patient sample relative to that of a control transcript by using the 2-DeltaDeltaCt calculation. The results of real-time RT-PCR for BCR/ABL transcripts are often analyzed by using plasmid DNA standard curves. In the present study, 79 BCR/ABL transcript-positive samples from CML patients who were being monitored for minimal residual disease by real-time quantitative RT-PCR were studied to determine whether the 2-DeltaDeltaCt approach was equivalent to the plasmid standard curve method. BCR/ABL P210 transcripts were quantitated using both the plasmid standard curve method and the 2-DeltaDeltaCt calculation. The comparison of both methods revealed a highly significant and linear correlation between the plasmid standard curve method and the 2-DeltaDeltaCt calculation (R2=0.98, P<0.0001). Furthermore, there was a reduction of preparation time, contamination risk, and reagent usage. The 2-DeltaDeltaCt calculation is a convenient alternative method to derive accurate quantitative information from real time PCR assays.
Diagn Mol Pathol 2006 Mar
PMID:Validation of the 2-DeltaDeltaCt calculation as an alternate method of data analysis for quantitative PCR of BCR-ABL P210 transcripts. 1653 70

The fibroblast growth factor receptor 1 (FGFR1) oncogene partner, FOP, is a centrosomal protein that is involved in the anchoring of microtubules (MTS) to subcellular structures. The protein was originally discovered as a fusion partner with FGFR1 in oncoproteins that give rise to stem cell myeloproliferative disorders. A subsequent proteomics screen identified FOP as a component of the centrosome. FOP contains a Lis-homology (LisH) motif found in more than 100 eukaryotic proteins. LisH motifs are believed to be involved in microtubule dynamics and organization, cell migration, and chromosome segregation; several of them are associated with genetic diseases. We report here a 1.6A resolution crystal structure of the N-terminal dimerization domain of FOP. The structure comprises an alpha-helical bundle composed of two antiparallel chains, each of them having five alpha-helices. The central part of the dimer contains the LisH domain. We further determined that the FOP LisH domain is part of a longer N-terminal segment that is required, albeit not sufficient, for dimerization and centrosomal localization of FOP.
J Mol Biol 2006 Jun 16
PMID:Structure of the N-terminal domain of the FOP (FGFR1OP) protein and implications for its dimerization and centrosomal localization. 1669 81

A point mutation in the JAK2 gene, a member of the tyrosine kinase family, was recently identified and shown to be associated with several myeloproliferative disorders. Several studies identified the same JAK2 point mutation (1,849G>T), resulting in the substitution of a valine to phenylalanine at codon 617 (V617F). We developed a simple and sensitive method to detect this mutation via polymerase chain reaction and probe dissociation analysis using the LightCycler platform, and we compared this method to existing restriction fragment-length polymorphism, direct sequencing, and amplification refractory mutation system methods. We found that the LightCycler method offered advantages of speed, reliability, and more straightforward interpretation over the restriction fragment-length polymorphism and sequencing approaches.
J Mol Diagn 2006 Jul
PMID:Detection of the JAK2 V617F mutation by LightCycler PCR and probe dissociation analysis. 1682 5

In early 2005, several groups of investigators studying myeloid malignancies described a novel somatic point mutation (V617F) in the conserved autoinhibitory pseudokinase domain of the Janus kinase 2 (JAK2) protein, which plays an important role in normal hematopoietic growth factor signaling. The V617F mutation is present in blood and marrow from a large proportion of patients with classic BCR/ABL-negative chronic myeloproliferative disorders and of a few patients with other clonal hematological diseases such as myelodysplastic syndrome, atypical myeloproliferative disorders, and acute myeloid leukemia. The JAK2 V617F mutation causes constitutive activation of the kinase, with deregulated intracellular signaling that mimics continuous hematopoietic growth factor stimulation. Within 7 months of the first electronic publication describing this new mutation, clinical molecular diagnostic laboratories in the United States and Europe began offering JAK2 mutation testing on a fee-for-service basis. Here, I review the various techniques used by research groups and clinical laboratories to detect the genetic mutation underlying JAK2 V617F, including fluorescent dye chemistry sequencing, allele-specific polymerase chain reaction (PCR), real-time PCR, DNA-melting curve analysis, pyrosequencing, and others. I also discuss diagnostic sensitivity, performance, and other practical concerns relevant to the clinical laboratorian in addition to the potential diagnostic utility of JAK2 mutation tests.
J Mol Diagn 2006 Sep
PMID:JAK2 V617F in myeloid disorders: molecular diagnostic techniques and their clinical utility: a paper from the 2005 William Beaumont Hospital Symposium on Molecular Pathology. 1693 78

We report a case of t(3;9)(q21;p24) in a patient with chronic idiopathic myelofibrosis (CIMF), a chronic myeloproliferative disorder (CMPD), initially detected by G-banding and fluorescent in situ hybridization (FISH) in an unstimulated culture of peripheral blood. Subsequent cytogenetic studies of bone marrow aspirates showed the presence and persistence of the same translocation. No additional cytogenetic abnormalities were found. This appears to be a unique translocation that has not been previously reported in the English literature, although both breakpoints, 3q21 and 9p24, are well known cancer-related breakpoints. The former is the mapped location of the ribophorin 1 (RPN1) gene, whereas the latter is the mapped location of the janus kinase 2 (JAK2) gene. This raises the possibility that disruption of one or both loci at the breakpoints of the presently described structural chromosomal rearrangement may be the primary event leading to the initiation and development of the hematopoietic disorder in this patient. It is not unreasonable to hypothesize that the juxtaposition of the RPN1 gene on 3q21 with the JAK2 gene on 9p24 leads to enhanced JAK2 activity. Additional studies will be needed to provide further support for or to disprove this hypothesis. To the best of our knowledge, this is the first reported case of CIMF associated with a reciprocal 3;9 translocation with the 3q21 and 9p24 breakpoints. The elucidation of the mechanism of leukemogenesis in CIMF may one day lead to successful targeted therapy in this hematopoietic disorder. It may also shed additional light on the diagnosis, prognosis and treatment of certain other cancers with similar genetic etiologies.
Exp Mol Pathol 2006 Dec
PMID:Chronic idiopathic myelofibrosis (CIMF) resulting from a unique 3;9 translocation disrupting the janus kinase 2 (JAK2) gene. 1695 46

Myeloproliferative disorders (MPDs) are clonal haematopoietic malignancies involving the abnormal proliferation of myeloid lineages. The World Health Organisation (WHO) classification of haematopoietic malignancies distinguishes MPDs from myelodysplastic/ myeloproliferative disorders and systemic mastocytosis. These malignancies frequently involve constitutive tyrosine kinase activity, resulting from either oncogenic fusion protein production or from point mutations. Chronic myelogenous leukaemia is the model used for studies of the consequences of such molecular defects. However, the heterogeneity of the clinical course of MPDs should be seen in a more rationale conceptual framework, including the many molecular events associated with these diseases. This review focuses on the various tyrosine kinase-related molecular mechanisms underlying both MPDs and rare diseases with myeloproliferative features. We pay particular attention to the newly identified JAK2 V617F mutation in polycythaemia vera, essential thrombocythaemia and idiopathic myelofibrosis and deal with disease heterogeneity and putative additional molecular mechanisms.
Cell Mol Life Sci 2006 Dec
PMID:Oncogenic mechanisms in myeloproliferative disorders. 1713 Oct 59


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