Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.10.2 (focal adhesion kinase)
44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have investigated two patients with acquired chromosomal rearrangements, a male presenting with a t(1;9)(p34;q34) and B cell progenitor acute lymphoid leukemia and a female presenting with a t(8;12)(p11;q15) and the 8p11 myeloproliferative syndrome. We determined that the t(1;9) fused ABL to SFPQ (also known as PSF), a gene mapping to 1p34 that encodes a polypyrimidine tract-binding protein-associated splicing factor. The t(8;12) fused CPSF6, a cleavage and polyadenylation specificity factor, to FGFR1. The fusions were confirmed by amplification of the genomic breakpoints and RT-PCR. The predicted oncogenic products of these fusions, SFPQ-ABL and CPSF6-FGFR1, are in-frame and encode the N-terminal domain of the partner protein and the entire tyrosine kinase domain and C-terminal sequences of ABL and FGFR1. SFPQ interacts with two FGFR1 fusion partners, ZNF198 and CPSF6, that are functionally related to the recurrent PDGFRalpha partner FIP1L1. Our findings thus identify a group of proteins that are important for pre-mRNA processing as fusion partners for tyrosine kinases in hematological malignancies.
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PMID:The t(1;9)(p34;q34) and t(8;12)(p11;q15) fuse pre-mRNA processing proteins SFPQ (PSF) and CPSF6 to ABL and FGFR1. 1820 9

In this study, we determined if in vitro resistance to prednisolone and dexamethasone could be circumvented by cortivazol or methylprednisolone, or reversed by meta-iodobenzylguanidine in pediatric lymphoblastic and myeloid leukemia. As there were strong correlations between the LC50 values (drug concentration inducing 50% leukemic cell kill, LCK) of the different glucocorticoids and median prednisolone/methylprednisolone, prednisolone/dexamethasone and prednisolone/cortivazol LC50 ratios did not differ between the leukemia subtypes, we conclude that none of the glucocorticoids had preferential anti-leukemic activity. Meta-iodobenzylguanidine however, partially reversed glucocorticoid resistance in 19% of the lymphoblastic leukemia samples.
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PMID:Circumvention of glucocorticoid resistance in childhood leukemia. 1839 53

JAK2 is a tyrosine kinase involved in cytokine signaling. The JAK2V617F point mutation, first described in 2005, results in constitutive activation of JAK2 and is now widely used as a diagnostic marker for Philadelphia chromosome negative myeloproliferative neoplasms. In recent years, more novel JAK2 mutations and fusion genes have been discovered in myeloproliferative neoplasms and other hematologic malignancies. This review aims to summarize the discovery and use of the JAK2V617F point mutation, other novel JAK2 mutations, and JAK2 translocations in diagnosing myeloproliferative neoplasms, acute myeloid leukemia, and acute lymphoid leukemia. JAK2 mutation testing is addressed, including the sensitivity and specificity of the different JAK2 mutation testing methods, clinical indications for use, and the use of quantitative JAK2 mutation testing for routine pathologic diagnosis, prognosis, and monitoring response to therapy. The relationship of JAK2 mutation to endogenous erythroid colony formation, thrombopoietin receptor mutation, polycythemia rubra vera-1 overexpression, and thrombopoietin receptor underexpression in myeloproliferative neoplasms are explored. Also discussed are the JAK2 inhibitors for clinical trials. Finally, the advantages of the newly proposed World Health Organization classification for myeloproliferative neoplasms are reviewed.
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PMID:The saga of JAK2 mutations and translocations in hematologic disorders: pathogenesis, diagnostic and therapeutic prospects, and revised World Health Organization diagnostic criteria for myeloproliferative neoplasms. 1853 68

The ABL-BCR fusion protein is a constitutively activated tyrosine kinase thought to play a central role in chronic myeloid leukemia (CML) and Philadelphia (Ph) chromosome acute lymphoid leukemia (ALL). Targeting the tyrosine kinase activity of ABL-BCR has been shown to be a promising therapeutic strategy in treating this disorder. Among the tyrosine kinase inhibitors, STI571 is a very effective therapeutic agent when administered to CML patients in the stable chronic phase. However, it has been reported that many CML patients with blast cell crisis treated with STI571 relapsed and became resistant to STI571. In order to understand the possible molecular mechanisms underlying STI571 resistance caused by ABL gene mutations, we investigated 19 patients (18 CML patients and 1 Ph (+) ALL patient) who either relapsed after initial response or had no response to STI571 treatment. We used polymerase chain reaction followed by restriction fragment length polymorphism (PCR-RFLP) analysis, dHPLC, and direct DNA sequencing to analyze any possible mutations in exons 5 to 9 of the ABL gene. Our results showed that 5 out of 19 patients had various mutations between exons 5 and 7 of the ABL gene. The Ph (+) ALL patient had a Glu255Lys mutation in exon 5 and a Thr315Ile mutation in exon 7. The Glu255Lys substitution has a G to A change, and the Thr315Ile substitution has a C to T change in the ABL gene. The other unique mutations found in this study include: Tyr253His, Met351Thr, GAA tri-nucleotides insertion, and Leu213Pro.
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PMID:Detection of BCR-ABL gene mutations in Philadelphia chromosome positive leukemia patients resistant to STI-571 cancer therapy. 1860 97

The aim of this study was to explore the molecule mechanism of resveratrol antileukaemia. The mouse lymphocytic leukemia L1210 cells were cultured and the expressions of pJAK1 and pSTAT3 protein in L1210 cells were detected by immunohistochemistry and immunoprecipitation in vitro. The mouse model with L1210 leukemia ascites carcinoma was established and activities of singal transduction pathway molecules pJAK1 and pSTAT3 were measured by Western blot and immunohistochemistry assay in vitro. The results indicated that resveratrol could significantly inhibit the JAK1/STAT3 signal transduction pathway, down-regulate expressions of pJAK1 and pSTAT3 and reduce the phosphorylation of JAK1 and STAT3 in a dose-and time-dependent manner. It is concluded that the resveratrol can regulate signal transduction pathway and reduce the activation of JAK1/STAT3 tyrosine phosphorylation significantly, and therefore resveratrol shows chemotherapeutic potential to leukaemia.
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PMID:[Regulatory effect of resveratrol on JAK1/STAT3 signal transduction pathway in leukemia]. 1871 58

It remains unresolved how different BCR-ABL transcripts differentially drive lymphoid and myeloid proliferation in Philadelphia chromosome-positive (Ph(+)) leukemias. We compared BCR-ABL transcript type and level with kinase domain (KD) mutation status, genotype, and phenotype in 1855 Ph(+) leukemias. Compared with e1a2/p190 BCR-ABL cases, de novo e13-e14a2/p210 Ph(+) lymphoid leukemia more frequently showed CML-type background, had higher blast-normalized BCR-ABL transcript levels, and more frequent persistent BCR-ABL transcript in the absence of detectable lymphoblasts. Secondary lymphoid blast transformation of CML was exclusively due to e13/e14a2/p210 BCR-ABL but was associated, at a much higher level than p210 myeloid transformation, with acquisition of new KD mutations and/or Ph genomic amplification. In contrast, myeloid blast transformation was more frequently accompanied by new acquisition of acute myeloid leukemia-type chromosomal aberrations, particularly involving the EVI1 and RUNX1 loci. Therefore, higher kinase activity by mutation, transcriptional up-regulation or gene amplification appears required for lymphoid transformation by p210 BCR-ABL.
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PMID:BCR-ABL fusion transcript types and levels and their interaction with secondary genetic changes in determining the phenotype of Philadelphia chromosome-positive leukemias. 1880 62

The Philadelphia (Ph) chromosome is characteristic of chronic myelogenous leukemia (CML), but it is also the most frequent cytogenetic abnormality in precursor B-lymphoblastic leukemia (ALL) of adults. The vast majority of CML patients have a BCR-ABL translocation that yields a 210 kD (p210) oncoprotein, whereas adult Ph-positive ALL cases can present with either a p190 or a p210 oncoprotein, or both. Considering that 30% of the patients with CML that progress to blast crisis will have a lymphoblastic presentation, adults presenting with a p210 ALL may have either a de novo ALL or CML presenting for the first time in lymphoblastic phase. To identify the distinguishing features, cases of p190-ALL, p210-ALL, and lymphoblastic CML were compared. In spite of significant overlap between the three entities, a number of features were found to aid in their differentiation. p210-ALL patients present at a younger age with blasts that frequently show loss of expression of CD34, whereas p190-ALL patients present with marked increase in peripheral blast percentage. Interestingly, bone marrow findings characteristic of a myeloproliferative disorder are specific, but are not sensitive for lymphoblastic CML. This study suggests that despite the similarities between these leukemias, p190-ALL, p210-ALL, and lymphoblastic phase CML likely represent three distinct diseases.
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PMID:The spectrum of adult B-lymphoid leukemias with BCR-ABL: molecular diagnostic, cytogenetic, and clinical laboratory perspectives. 1893 38

CML is an hematopoietic stem cell disease characterized by the t(9;22) (q34;q11) translocation encoding the oncoprotein p210BCR-ABL. The effect of acadesine (AICAR, 5-Aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside) a compound with known antileukemic effect on B cell chronic lymphoblastic leukemia (B-CLL) was investigated in different CML cell lines. Acadesine triggered loss of cell metabolism in K562, LAMA-84 and JURL-MK1 and was also effective in killing imatinib-resistant K562 cells and Ba/F3 cells carrying the T315I-BCR-ABL mutation. The anti-leukemic effect of acadesine did not involve apoptosis but required rather induction of autophagic cell death. AMPK knock-down by Sh-RNA failed to prevent the effect of acadesine, indicating an AMPK-independent mechanism. The effect of acadesine was abrogated by GF109203X and Ro-32-0432, both inhibitor of classical and new PKCs and accordingly, acadesine triggered relocation and activation of several PKC isoforms in K562 cells. In addition, this compound exhibited a potent anti-leukemic effect in clonogenic assays of CML cells in methyl cellulose and in a xenograft model of K562 cells in nude mice. In conclusion, our work identifies an original and unexpected mechanism by which acadesine triggers autophagic cell death through PKC activation. Therefore, in addition to its promising effects in B-CLL, acadesine might also be beneficial for Imatinib-resistant CML patients.
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PMID:Acadesine kills chronic myelogenous leukemia (CML) cells through PKC-dependent induction of autophagic cell death. 1992 52

The serine/threonine Pim kinases are up-regulated in specific hematologic neoplasms, and play an important role in key signal transduction pathways, including those regulated by MYC, MYCN, FLT3-ITD, BCR-ABL, HOXA9, and EWS fusions. We demonstrate that SMI-4a, a novel benzylidene-thiazolidine-2, 4-dione small molecule inhibitor of the Pim kinases, kills a wide range of both myeloid and lymphoid cell lines with precursor T-cell lymphoblastic leukemia/lymphoma (pre-T-LBL/T-ALL) being highly sensitive. Incubation of pre-T-LBL cells with SMI-4a induced G1 phase cell-cycle arrest secondary to a dose-dependent induction of p27(Kip1), apoptosis through the mitochondrial pathway, and inhibition of the mammalian target of rapamycin C1 (mTORC1) pathway based on decreases in phospho-p70 S6K and phospho-4E-BP1, 2 substrates of this enzyme. In addition, treatment of these cells with SMI-4a was found to induce phosphorylation of extracellular signal-related kinase1/2 (ERK1/2), and the combination of SMI-4a and a mitogen-activated protein kinase kinase 1/2 (MEK1/2) inhibitor was highly synergistic in killing pre-T-LBL cells. In immunodeficient mice carrying subcutaneous pre-T-LBL tumors, treatment twice daily with SMI-4a caused a significant delay in the tumor growth without any change in the weight, blood counts, or chemistries. Our data suggest that inhibition of the Pim protein kinases may be developed as a therapeutic strategy for the treatment of pre-T-LBL.
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PMID:A small molecule inhibitor of Pim protein kinases blocks the growth of precursor T-cell lymphoblastic leukemia/lymphoma. 1996 90

Entire ABL1 gene deletion without BCR/ABL1 rearrangement is a rare phenomenon, with only four cases previously reported. Here we describe a fifth case of ABL1 deletion without BCR/ABL1 rearrangement in an adolescent patient with precursor B-cell lymphoblastic leukemia (B-ALL) and review the relevant literature. It is not clear how ABL1 deletion affects leukemogenesis; however, it is plausible that ABL1 deletion without BCR/ABL1 rearrangement is a rare but recurrent genetic abnormality in precursor B-ALL patients. Further studies are needed to evaluate the extent of the submicroscopic defects in chromosome 9 including ABL1 gene deletion, as well as treatment response and prognosis in long-term follow-up of such patients.
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PMID:ABL1 gene deletion without BCR/ABL1 rearrangement in a young adolescent with precursor B-cell acute lymphoblastic leukemia: clinical study and literature review. 2008 57


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