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 acquired JAK2 V617F mutation is observed in the majority of patients with BCR-ABL1 negative chronic myeloproliferative neoplasms (MPN). BCR-ABL1 negative MPN displays myeloproliferation with an elevated leucocyte alkaline phosphatase (LAP) activity, a neutrophil activation marker. We tried to separate the downstream signalling of JAK2 V617F to stimulate myeloproliferation and LAP activity. NB4, a myeloid lineage cell line, was transduced with Jak2 V617F mutation or wild-type Jak2. We found that Jak2 V617F mutation, but not wild-type Jak2 enhanced LAP expression in NB4-derived neutrophils and proliferation of NB4 cells. JAK2 V617F induces constitutive phosphorylation of STAT3 and STAT5, and uses signalling targets such as Ras/MEK/ERK and PI3K/Akt pathways. By using MEK1/2 inhibitor U0126, PI3K inhibitor LY294002, and STAT3 or STAT5 siRNAs, JAK2 V617F was found to specifically use the STAT3 pathway to enhance LAP expression, while STAT5, Ras/MEK/ERK and PI3K/Akt, but not STAT3 pathways, were able to stimulate cell proliferation. These data strongly suggest that JAK2 V617F uses distinct signalling pathways to induce typical pathological features of MPN, such as high LAP activity and enhanced cell proliferation.
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PMID:JAK2 V617F uses distinct signalling pathways to induce cell proliferation and neutrophil activation. 2055 73

The BCR-ABL1 oncoprotein transforms pluripotent HSCs and initiates chronic myeloid leukemia (CML). Patients with early phase (also known as chronic phase [CP]) disease usually respond to treatment with ABL tyrosine kinase inhibitors (TKIs), although some patients who respond initially later become resistant. In most patients, TKIs reduce the leukemia cell load substantially, but the cells from which the leukemia cells are derived during CP (so-called leukemia stem cells [LSCs]) are intrinsically insensitive to TKIs and survive long term. LSCs or their progeny can acquire additional genetic and/or epigenetic changes that cause the leukemia to transform from CP to a more advanced phase, which has been subclassified as either accelerated phase or blastic phase disease. The latter responds poorly to treatment and is usually fatal. Here, we discuss what is known about the molecular mechanisms leading to blastic transformation of CML and propose some novel therapeutic approaches.
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PMID:Chronic myeloid leukemia: mechanisms of blastic transformation. 2059 75

The BCR-ABL1 fusion gene results from a reciprocal translocation rearrangement, t(9;22)(q34;q11.2), and is a hallmark of chronic myeloid leukemia (CML). The breakpoint on chromosome 9 is mostly 5' to ABL1 exon 2, whereas on chromosome 22, the breakpoint can occur in various regions involving the major breakpoint cluster region (M-bcr) in CML and the minor breakpoint cluster region (m-bcr) in acute lymphoblastic leukemia. Described here is a rare case of Philadelphia-positive CML with intronic splice sites. This atypical BCR-ABL1 transcript was detected along with a classic e13a2 transcript, using reverse transcription polymerase chain reaction (RT-PCR). Nucleotide sequence analysis revealed a joining of BCR intron 13 with ABL1 intron 1a. Both transcripts were detected when the patient was on hydroxyurea treatment; with imatinib mesylate therapy, the atypical transcript disappeared. To our knowledge, this is the first report of BCR-ABL1 transcript with breakpoint occurring within both BCR and ABL1 introns and fusion of intronic sequences from both BCR and ABL1 genes.
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PMID:A unique BCR-ABL1 transcript with the insertion of intronic sequence from BCR and ABL1 genes in a patient with Philadelphia-positive chronic myeloid leukemia: a case study. 2063 71

As a result of the excellent responses achieved in chronic phase chronic myeloid leukemia since the introduction of imatinib, sensitive techniques such as reverse transcriptase real-time PCR are warranted to monitor patients receiving tyrosine kinase inhibitors (TKI). Our objective was to determine the value of molecular monitoring Ph-positive leukemias under dasatinib treatment. We used real-time PCR and ABL1 kinase domain sequencing on sequential samples from 11 patients with Philadelphia-positive leukemias who received dasatinib. We were able to detect pre-existing mutations in the kinase domain of BCR-ABL1 in four patients, particularly in patients with high BCR-ABL1 transcript levels. Most mutations disappeared with dasatinib, however, in five patients a clone with T315I appeared during dasatinib treatment. We conclude that sensitive molecular monitoring with real-time PCR for BCR-ABL1 transcripts and mutation screening of the ABL1 kinase domain of patients with Philadelphia-positive leukemias are valuable for patient management, however, mutation findings should be interpreted with caution, as mutant clones not always behave in vivo as predicted by in vitro assays.
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PMID:Molecular monitoring and mutation analysis of patients with advanced phase CML and Ph+ ALL receiving dasatinib. 2065 55

Non-receptor protein tyrosine kinases are responsible for signal transduction during many physiologic cellular processes, including cell growth and proliferation, apoptosis, differentiation, regulation of actin cytoskeleton, cell shape, adhesion, motility and migration. Aberrant activity of protein tyrosine kinases (acquired as a result of chromosomal translocation or point mutation) has been implicated in the stimulation of cancer growth and progression, the induction of drug-resistance, tumour neovascularization, tissue invasion, extravasation and the formation of metastases. Small molecule tyrosine kinase inhibitors interfere with these pathophysiological circuits by blocking the signalling cascades triggered by the aberrantly activated protein tyrosine kinases (e.g. BCR-ABL1, FIP1L1-PDGFRA or ETV6-PDGFRB).Tyrosine kinase inhibitors (imatinib, nilotinib, dasatinib) now belong to established anti-cancer agents with clinical activity in patients with CML, Ph+ ALL, and myeloid neoplasms with overexpression of PDGFRA, PDGFRB and wild-type KIT. New generation tyrosine kinase inhibitors (e.g. dasatinib) with extended activity against SRC and EPH kinases belong to promising anti-cancer agents with documented preclinical activity in several solid tumours (e.g. prostate cancer).
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PMID:[ABL1, SRC and other non-receptor protein tyrosine kinases as new targets for specific anticancer therapy]. 2080 17

ABL-family proteins comprise one of the best conserved branches of the tyrosine kinases. Each ABL protein contains an SH3-SH2-TK (Src homology 3-Src homology 2-tyrosine kinase) domain cassette, which confers autoregulated kinase activity and is common among nonreceptor tyrosine kinases. This cassette is coupled to an actin-binding and -bundling domain, which makes ABL proteins capable of connecting phosphoregulation with actin-filament reorganization. Two vertebrate paralogs, ABL1 and ABL2, have evolved to perform specialized functions. ABL1 includes nuclear localization signals and a DNA binding domain through which it mediates DNA damage-repair functions, whereas ABL2 has additional binding capacity for actin and for microtubules to enhance its cytoskeletal remodeling functions. Several types of posttranslational modifications control ABL catalytic activity, subcellular localization, and stability, with consequences for both cytoplasmic and nuclear ABL functions. Binding partners provide additional regulation of ABL catalytic activity, substrate specificity, and downstream signaling. Information on ABL regulatory mechanisms is being mined to provide new therapeutic strategies against hematopoietic malignancies caused by BCR-ABL1 and related leukemogenic proteins.
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PMID:ABL tyrosine kinases: evolution of function, regulation, and specificity. 2084 68

The discovery of JAK2V617F has rejuvenated interest in Janus kinase (JAK)-signal transducer and activator of transcription (STAT), both as an oncogenic pathway and a drug target in BCR-ABL1-negative myeloproliferative neoplasms (MPN). However, the complexity of these diseases in terms of both clonal structure and mutation repertoire makes it unlikely that JAK inhibitor therapy will replicate what has been achieved with imatinib in chronic myeloid leukemia. Consistent with this view, JAK inhibitor therapy in myelofibrosis has not yet produced complete or partial remissions. However, most patients treated with a JAK2 (TG101348) or JAK1/2 (INCB018424) inhibitor experienced substantial improvement in constitutional symptoms and reduction in spleen size; the mechanism of action for INCB018424 includes anti-JAK1-mediated downregulation of proinflammatory cytokines. These observations complicate the choice of primary end points in clinical trials that would be robust enough to support regulatory approval. TG101348 and INCB018424 are the vanguard of JAK inhibitor therapy in myelofibrosis, but newer JAK inhibitors might have a broader spectrum of activity; preliminary results with CYT387 suggest responses in both anemia and splenomegaly. Outstanding issues regarding these drugs include identification of the optimal dosing strategy, their role (if any) in the treatment of polycythemia vera or essential thrombocythemia, and the potential for combining them with other therapeutic agents.
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PMID:JAK inhibitor therapy for myelofibrosis: critical assessment of value and limitations. 2107 13

ABL gene translocations create constitutively active tyrosine kinases that are causative in chronic myeloid leukemia, acute lymphocytic leukemia and other hematopoietic malignancies. Consistent retention of ABL SH3/SH2 autoinhibitory domains, however, suggests that these leukemogenic tyrosine kinase fusion proteins remain subject to regulation. We resolve this paradox, demonstrating that BCR-ABL1 kinase activity is regulated by RIN1, an ABL SH3/SH2 binding protein. BCR-ABL1 activity was increased by RIN1 overexpression and decreased by RIN1 silencing. Moreover, Rin1(-/-) bone marrow cells were not transformed by BCR-ABL1, ETV6-ABL1 or BCR-ABL1(T315I), a patient-derived drug-resistant mutant, as judged by growth factor independence. Rescue by ectopic RIN1 verified a cell autonomous mechanism of collaboration with BCR-ABL1 during transformation. Sensitivity to the ABL kinase inhibitor imatinib was increased by RIN1 silencing, consistent with RIN1 stabilization of an activated BCR-ABL1 conformation having reduced drug affinity. The dependence on activation by RIN1 to unleash full catalytic and cell transformation potential reveals a previously unknown vulnerability that could be exploited for treatment of leukemic cases driven by ABL translocations. The findings suggest that RIN1 targeting could be efficacious for imatinib-resistant disease and might complement ABL kinase inhibitors in first-line therapy.
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PMID:ABL fusion oncogene transformation and inhibitor sensitivity are mediated by the cellular regulator RIN1. 2110 29

Myeloproliferative neoplasms (MPN) are clonal haemopoietic progenitor cell disorders characterized by the proliferation of one or more of the haemopoietic lineages (myeloid, erythroid and/or megakaryocytic). The MPNs include eight haematological disorders: chronic myelogenous leukemia (CML), polycythemia vera (PV), essential thrombocythemia (ET), primary myelofibrosis (PMF), systemic mastocytosis (SM), chronic eosinophilic leukemia, not otherwise specified (CEL, NOS), chronic neutrophilic leukemia (CNL), and unclassifiable MPN (MPN, U). Therapeutic interventions for MPNs include the use of tyrosine kinase inhibitors (TKIs) for BCR-ABL1(+) CML and JAK2 inhibitors for PV, ET and PMF. Histone deacetylase inhibitors (HDACi) are a novel class of drugs capable of altering the acetylation status of both histone and non-histone proteins, thereby affecting a repertoire of cellular functions in neoplastic cells including proliferation, differentiation, immune responses, angiogenesis and survival. Preliminary studies indicate that HDACi when used in combination with tyrosine kinase or JAK2 inhibitors may overcome resistance to the latter agents and enhance the pro-apoptotic effects on MPN cells. This review provides a review of pre-clinical and clinical studies that have explored the use of HDACi as potential therapeutics for MPNs.
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PMID:Deactylase inhibition in myeloproliferative neoplasms. 2112 42

B-precursor acute lymphoblastic leukemia (B-ALL) is the most common childhood malignancy and remains a leading cause of death in children and young adults. Current therapeutic approaches involve intensive combination chemotherapy, which fails in up to one quarter of patients. New treatment approaches directed against rational therapeutic targets are required. Recent genomic profiling of ALL has identified several genetic alterations associated with a high risk of treatment failure. Deletion or sequence mutation of the lymphoid transcription factor gene IKZF1 (IKAROS) is associated with a high rate of leukemic relapse, and testing for IKZF1 alterations at diagnosis may aid risk stratification. A subset of B-ALL patients with IKZF1 alterations have a transcriptional profile similar to BCR-ABL1-positive ALL, and these patients commonly have novel rearrangements and mutations resulting in aberrant cytokine receptor signaling and activation of kinase signaling cascades, including rearrangement of CRLF2 and activating mutations of Janus kinases (JAK1 and JAK2). JAK inhibitor therapy is under investigation in children with relapsed and refractory malignancies, including leukemia.
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PMID:New strategies in acute lymphoblastic leukemia: translating advances in genomics into clinical practice. 2114 16


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