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)

The mammalian genome contains several hundred microRNAs that regulate gene expression through modulation of target mRNAs. Here, we report a fragile chromosomal region lost in specific hematopoietic malignancies. This 7 Mb region encodes about 12% of all genomic microRNAs, including miR-203. This microRNA is additionally hypermethylated in several hematopoietic tumors, including chronic myelogenous leukemias and some acute lymphoblastic leukemias. A putative miR-203 target, ABL1, is specifically activated in these hematopoietic malignancies in some cases as a BCR-ABL1 fusion protein (Philadelphia chromosome). Re-expression of miR-203 reduces ABL1 and BCR-ABL1 fusion protein levels and inhibits tumor cell proliferation in an ABL1-dependent manner. Thus, miR-203 functions as a tumor suppressor, and re-expression of this microRNA might have therapeutic benefits in specific hematopoietic malignancies.
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PMID:Genetic and epigenetic silencing of microRNA-203 enhances ABL1 and BCR-ABL1 oncogene expression. 2707 Jul 7

Genetic alterations causing constitutive tyrosine kinase activation are observed in a broad spectrum of cancers. Thus far, these mutant kinases have been localized to the plasma membrane or cytoplasm, where they engage proliferation and survival pathways. We report that the NUP214-ABL1 fusion is unique among these because of its requisite localization to the nuclear pore complex for its transforming potential. We show that NUP214-ABL1 displays attenuated transforming capacity as compared to BCR-ABL1 and that NUP214-ABL1 preferentially transforms T cells, which is in agreement with its unique occurrence in T cell acute lymphoblastic leukemia. Furthermore, NUP214-ABL1 differs from BCR-ABL1 in subcellular localization, initiation of kinase activity, and signaling and lacks phosphorylation on its activation loop. In addition to delineating an unusual mechanism for kinase activation, this study provides new insights into the spectrum of chromosomal translocations involving nucleoporins by indicating that the nuclear pore context itself may play a central role in transformation.
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PMID:Kinase activation and transformation by NUP214-ABL1 is dependent on the context of the nuclear pore. 1861 52

The NUP214-ABL1 fusion kinase has recently been identified in 6% of patients with T-cell acute lymphoblastic leukemia. In contrast to the more common oncogenic ABL1 fusion BCR-ABL1, NUP214-ABL1 localizes to the nuclear pore complexes and has attenuated transforming properties in hematopoietic cells and in mouse bone marrow transplant models. We have performed a thorough biochemical comparative analysis of NUP214-ABL1 and BCR-ABL1 and show that, despite their common tyrosine kinase domain, the two fusion proteins differ in many critical catalytic properties. NUP214-ABL1 has lower in vitro tyrosine kinase activity, which is in agreement with the absence of phosphorylation on its activation loop. NUP214-ABL1 was more sensitive to imatinib (Glivec) than BCR-ABL1 in vitro and in cells, indicating a different activation state and conformation of the two ABL1 fusion kinases. Using a peptide array, we identified differences in the spectrum and efficiency of substrate peptide phosphorylation and a differential involvement of Src kinases in downstream signaling. These results clearly indicate that different fusion partners of the same kinase can determine not only localization, but also critical functional properties of the enzyme such as inhibitor sensitivity and substrate preference, with subsequent differences in downstream signaling effectors and likely consequences in disease pathogenesis.
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PMID:Intrinsic differences between the catalytic properties of the oncogenic NUP214-ABL1 and BCR-ABL1 fusion protein kinases. 1878 40

Therapeutically validated oncoproteins in myeloproliferative neoplasms (MPN) include BCR-ABL1 and rearranged PDGFR proteins. The latter are products of intra- (e.g. FIP1L1-PDGFRA) or inter-chromosomal (e.g. ETV6-PDGFRB) gene fusions. BCR-ABL1 is associated with chronic myelogenous leukaemia (CML) and mutant PDGFR with an MPN phenotype characterized by eosinophilia and in addition, in case of FIP1L1-PDGFRA, bone marrow mastocytosis. These genotype-phenotype associations have been effectively exploited in the development of highly accurate diagnostic assays and molecular targeted therapy. It is hoped that the same will happen in other MPN with specific genetic alterations: polycythemia vera (JAK2 V617F and other JAK2 mutations), essential thrombocythemia (JAK2V617F and MPL515 mutations), primary myelofibrosis (JAK2 V617F and MPL515 mutations), systemic mastocytosis (KITD816V and other KIT mutations) and stem cell leukaemia/lymphoma (ZNF198-FGFR1 and other FGFR1 fusion genes). The current review discusses the above listed mutant molecules in the context of their value as drug targets.
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PMID:Molecular drug targets in myeloproliferative neoplasms: mutant ABL1, JAK2, MPL, KIT, PDGFRA, PDGFRB and FGFR1. 1917 93

Treatment responses to imatinib vary among patients with chronic myeloid leukemia (CML), and definitions of treatment failure and suboptimal response have been published. This article discusses monitoring and treatment of patients with CML after failure of or suboptimal response to imatinib therapy. We reviewed articles listed on PubMed from January 1, 2002, to July 31, 2008, and abstracts from the 2007 Annual Meeting of the American Society of Hematology. Search terms used were chronic myeloid/myelogenous leukemia, imatinib, and BCR-ABL. To enable early recognition of suboptimal responses, patients should be frequently monitored according to published guidelines, including cytogenetic analysis every 6 months until a complete response is achieved and molecular monitoring every 3 months from the start of therapy or monthly if an increasing BCR-ABL1 transcript level is detected. Mutational analysis of BCR-ABL1 may assist with treatment selection. A recent survey suggests that a notable proportion of physicians do not follow treatment guidelines and that broader communication is required. Recent recommendations state that, in patients whose response to imatinib at 400 mg/d is suboptimal, the dose should be increased, whereas alternative therapies, such as dasatinib, nilotinib, and allogeneic stem cell transplant (in eligible patients), and imatinib dose escalation should be considered after imatinib failure. However, clinical data are lacking to confirm this sequence of treatments, and introducing alternative therapies at an earlier stage of treatment, for example, after a suboptimal response, may produce better long-term outcomes in a higher proportion of patients. Patient and disease characteristics should be carefully considered to optimize treatment strategy for CML.
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PMID:Suboptimal response to or failure of imatinib treatment for chronic myeloid leukemia: what is the optimal strategy? 1918 50

BCR-ABL1 transcript numbers were monitored in 161 patients who started treatment with imatinib early after diagnosis of chronic myeloid leukaemia in chronic phase and achieved complete cytogenetic responses (CCyR). A confirmed doubling in BCR-ABL1/ABL1 transcript levels was found to be a significant factor for predicting loss of CCyR [relative risk (RR) 8.3, P < 0.0001] and progression to advanced phase (RR 0.07, P = 0.03) provided that the eventual BCR-ABL1/ABL1 transcript level exceeded 0.05%; increases that never exceeded 0.05% had no predictive value. The finding of a kinase domain mutation in a patient in CCyR, though rare, also predicted for loss of CCyR.
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PMID:Does a rise in the BCR-ABL1 transcript level identify chronic phase CML patients responding to imatinib who have a high risk of cytogenetic relapse? 1934 97

Patients not in complete cytogenetic response (CCyR) continuously face the competing possibilities of eventually achieving a cytogenetic response versus progressing. We analyzed the probability of achieving a CCyR, major molecular response, and progression in 258 patients with chronic myeloid leukemia in early chronic phase at 3, 6, and 12 months from imatinib start. The initial imatinib dose was 800 mg/day in 208 (81%) and 400 mg/day in 50 (19%) patients. For patients not in CCyR, the probability of achieving CCyR (P = .002) or major molecular response (P = .004) significantly decreased, whereas the risk of progression increased (P = .16) at each time point. Patients with a BCR-ABL1/ABL1 ratio greater than 1% to 10% after 3 months of imatinib had a 92% probability of achieving CCyR with continued therapy, similar to the 98% for those with 1% or less, but their risk of progression (11%) was almost 3-fold that of patients with a BCR-ABL1/ABL1 transcript ratio of 1% or less (4%) and similar to that of patients with transcript levels more than 10% (13%). These results suggest that patients not in CCyR after 12 months on imatinib have a higher risk of progression. This risk is discernible as early as 3 months into imatinib therapy by molecular analysis and may provide the rationale to institute therapies that render higher rates of early response.
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PMID:Delayed achievement of cytogenetic and molecular response is associated with increased risk of progression among patients with chronic myeloid leukemia in early chronic phase receiving high-dose or standard-dose imatinib therapy. 1936 33

Data on angiogenesis in the bone marrow of BCR-ABL1-negative myeloproliferative neoplasm (MPN) patients suggest an increase of the microvessel density (MVD) and vascular endothelial growth factor (VEGF) expression, but relations to the JAK2-V617F status remain controversial. We performed immunohistochemical studies of MVD and VEGF-expression in 100 MPN, including 24 essential thrombocythemia- (ET), 46 polycythemia vera- (PV), 26 primary myelofibrosis- (PMF), four myelodysplastic (MDS)/MPN- and 20 control reactive bone marrow cases, and correlated these findings with biological and clinical key data and the JAK2-V617F status. We found significantly increased MVD, particularly that assessed by CD105, and VEGF expression in MPN compared to controls (PMF > PV > MDS/MPN > ET). We observed stronger association between CD105-MVD and VEGF expression, fibrosis, and JAK2-V617F mutant allele burden, compared to CD34-MVD. MVD was strongly increased in MPN with high JAK2-V617F mutant allele burden. Our study highlights the importance of newly formed CD105+ vessels in the bone marrow of MPN patients, and indicates that assessment of CD105-MVD better reflects angiogenic activity in MPN. In addition, it provides evidence that despite the fact that angiogenesis is generally independent of the JAK2-V617F status in MPN, new vessel formation might be linked to Jak2 effects in some cases with high JAK2-V617F mutant allele burden.
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PMID:Angiogenesis and vascular endothelial growth factor-/receptor expression in myeloproliferative neoplasms: correlation with clinical parameters and JAK2-V617F mutational status. 1946 75

Pediatric acute lymphoblastic leukemia (ALL) is a heterogeneous disease consisting of distinct clinical and biological subtypes that are characterized by specific chromosomal abnormalities or gene mutations. Mutation of genes encoding tyrosine kinases is uncommon in ALL, with the exception of Philadelphia chromosome-positive ALL, where the t(9,22)(q34;q11) translocation encodes the constitutively active BCR-ABL1 tyrosine kinase. We recently identified a poor prognostic subgroup of pediatric BCR-ABL1-negative ALL patients characterized by deletion of IKZF1 (encoding the lymphoid transcription factor IKAROS) and a gene expression signature similar to BCR-ABL1-positive ALL, raising the possibility of activated tyrosine kinase signaling within this leukemia subtype. Here, we report activating mutations in the Janus kinases JAK1 (n = 3), JAK2 (n = 16), and JAK3 (n = 1) in 20 (10.7%) of 187 BCR-ABL1-negative, high-risk pediatric ALL cases. The JAK1 and JAK2 mutations involved highly conserved residues in the kinase and pseudokinase domains and resulted in constitutive JAK-STAT activation and growth factor independence of Ba/F3-EpoR cells. The presence of JAK mutations was significantly associated with alteration of IKZF1 (70% of all JAK-mutated cases and 87.5% of cases with JAK2 mutations; P = 0.001) and deletion of CDKN2A/B (70% of all JAK-mutated cases and 68.9% of JAK2-mutated cases). The JAK-mutated cases had a gene expression signature similar to BCR-ABL1 pediatric ALL, and they had a poor outcome. These results suggest that inhibition of JAK signaling is a logical target for therapeutic intervention in JAK mutated ALL.
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PMID:JAK mutations in high-risk childhood acute lymphoblastic leukemia. 1947 Apr 74

Chronic myeloid leukemia (CML) is a myeloproliferative disorder characterized by a triphasic clinical course, the morphologic expansion of a terminally differentiated myeloid cell and the presence of the BCR-ABL1 fusion gene, the hallmark of CML. The fusion gene is usually, but not always, associated with a Philadelphia chromosome, the result of a reciprocal exchange of genetic material between chromosome 22 and chromosome 9, which leads to the production of the activated BCR-ABL1 gene and oncoprotein. The breakpoint in the BCR gene occurs commonly downstream of exons e13 or e14 (M-BCR) and less frequently downstream of exons e1 and e2 (m-BCR). Less than 1% of cases carry a breakpoint downstream of exon 6 or 8 ("variant fusion genes") or exon 19 (mu-BCR). Breakpoints in the ABL1 gene cluster upstream of exon a2 (or of exon a3 in less than 5% of patients with CML). Conventional cytogenetic, fluorescence in situ hybridization, and molecular testing for the BCR-ABL1 fusion gene are key investigations for the diagnosis and monitoring of CML. Treatment using tyrosine kinase inhibitors has revolutionized the management of CML with hematologic and cytogenetic response within 12-18 months observed in >85% of patients. Nevertheless, between 15 and 20% of patients may evolve to blastic phase. Measurement of low level or "minimal" residual disease using molecular tests is becoming the gold-standard approach to measure response to therapy due to its higher sensitivity compared to other routine techniques. The technical aspects and clinical applications of molecular monitoring will be the main focus of this article.
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PMID:Technical aspects and clinical applications of measuring BCR-ABL1 transcripts number in chronic myeloid leukemia. 1954 76


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