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)

Oncogenic activation of tyrosine kinase signaling pathway is recurrent in human leukemia. To gain insight into the oncogenic process leading to acute megakaryoblastic leukemia (AMKL), we performed sequence analyses of a subset of oncogenes known to be activated in human myeloid and myeloproliferative disorders. In a series of human AMKL samples from both Down syndrome and non-Down syndrome patients, mutations were identified within KIT, FLT3, JAK2, JAK3, and MPL genes, with a higher frequency in DS than in non-DS patients. The novel mutations were analyzed using BaF3 cells, showing that JAK3 mutations were activating mutations. Finally, we report a novel constitutively active MPL mutant, MPLT487A, observed in a non-Down syndrome childhood AMKL that induces a myeloproliferative disease in mouse bone marrow transplantation assay.
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PMID:Activating mutations in human acute megakaryoblastic leukemia. 1875 84

The in vitro cultures of erythroid (BFU-E) and megakaryocytic (CFU-Meg) progenitors have been useful diagnostic tools in myeloproliferative disorders (MPD). However, after the discovery of the JAK2V617F mutation, their diagnostic role has been uncertain. In this single-centre retrospective study we analyzed JAK2V617F mutation in 58 ET and 42 PV patients diagnosed according to WHO criteria and compared the results with those of colony forming assays with special emphasis on CFU-Meg growth. 91% of PV and 57% of ET patients had JAK2V617F mutation and they all showed spontaneous BFU-E growth. However, endogenous BFU-E formation was also seen in nine JAK2V617F mutation negative patients displaying also a normal JAK2 exon 12 allele. Endogeneous CFU-Meg colony formation was found in 59% of PV and 53% of the ET patients. A subgroup of ET patients (n=7) displayed sole spontaneous CFU-Meg growth without spontaneous BFU-E growth. They all were JAK2 mutation negative, but one of them had MPL mutation. In conclusion, in vitro cultures of haematopoietic progenitors are sensitive diagnostic tools in the present group of 100 MPD patients revealing also JAK2 mutation negative ET and PV patients displaying sole spontaneous CFU-Meg or BFU-E growth.
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PMID:JAK2V617F mutation and spontaneous megakaryocytic or erythroid colony formation in patients with essential thrombocythaemia (ET) or polycythaemia vera (PV). 1876 Apr 72

Primary myelofibrosis (PMF) is a clonal stem cell disorder that manifests clinically as anemia, splenomegaly due to extramedullary hematopoiesis, leukoerythroblastosis, and constitutional symptoms, which are the clinical hallmarks of PMF. Within the past three years it has been determined that a single, recurrent, somatic mutation in the gene encoding the cytoplasmic tyrosine kinase Janus kinase 2 (JAK2) occurs in the majority of patients with PMF, and more recently, activating mutations in the gene encoding the thrombopoietin receptor MPL have also been identified in a subset of PMF patients. These discoveries have yielded important insights into the pathogenesis of PMF and have brought about the first opportunity for rationally targeted therapy for this disorder. Here we present an updated review of the pathogenesis, definition, and treatment of PMF in light of the discovery of JAK2 and MPL mutations, as well as other recent work in the myeloproliferative neoplasm field.
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PMID:Primary myelofibrosis: update on definition, pathogenesis, and treatment. 1894 94

We developed a real-time copy number polymerase chain reaction assay for deletions on chromosome 20q (del20q), screened peripheral blood granulocytes from 664 patients with myeloproliferative disorders, and identified 19 patients with del20q (2.9%), of which 14 (74%) were also positive for JAK2-V617F. To examine the temporal relationship between the occurrence of del20q and JAK2-V617F, we performed colony assays in methylcellulose, picked individual burst-forming units-erythroid (BFU-E) and colony-forming units-granulocyte (CFU-G) colonies, and genotyped each colony individually for del20q and JAK2-V617F. In 2 of 9 patients, we found that some colonies with del20q carried only wild-type JAK2, whereas other del20q colonies were JAK2-V617F positive, indicating that del20q occurred before the acquisition of JAK2-V617F. However, in colonies from 3 of 9 patients, we observed the opposite order of events. The lack of a strict temporal order of occurrence makes it doubtful that del20q represents a predisposing event for JAK2-V617F. In 2 patients with JAK2-V617F and 1 patient with MPL-W515L, microsatellite analysis revealed that del20q affected chromosomes of different parental origin and/or 9pLOH occurred at least twice. The fact that rare somatic events, such as del20q or 9pLOH, occurred more than once in subclones from the same patients suggests that the myeloproliferative disorder clone carries a predisposition to acquiring such genetic alterations.
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PMID:Clonal analysis of deletions on chromosome 20q and JAK2-V617F in MPD suggests that del20q acts independently and is not one of the predisposing mutations for JAK2-V617F. 1904 81

Acquired sideroblastic anemia with unilineage dysplasia (WHO RARS) is a clonal stem cell disorder characterized by erythroid dysplasia, mitochondrial accumulation of mitochondrial ferritin, defective erythroid maturation and anemia. A fraction of these patients also show elevated platelet counts; since 2001 this has been defined as RARS with marked thrombocytosis (RARS-T). It has recently been described that around half of RARS-T patients, along with a small subset of other MDS and mixed myelodysplastic/ myeloproliferative disorders, carry the JAK2 mutation, and that MPL mutations are found in single patients. Clinically, RARS-T patients show features of both RARS, essential thrombocythmia (ET) and to some extent also myelofibrosis. However, the degree of anemia and overall survival is more similar to RARS than myeloproliferative disorders. The occurrence of JAK2 mutations and features of ET in RARS is too frequent to be the result of chance only, and it is possible that this link may provide a key to an increased understanding of the genetic abnormalities causing ring sideroblast formation.
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PMID:The role of JAK2 mutations in RARS and other MDS. 1907 58

Essential thrombocythemia (ET) is a hematopoietic disorder that manifests clinically as thrombocytosis, and patients with ET are at increased risk for developing thrombosis, myelofibrosis, and transformation to acute myeloid leukemia. Although ET was recognized as a distinct clinical syndrome more than 6 decades ago and was classified as a myeloproliferative neoplasm (MPN) by William Dameshek in 1951, the molecular pathogenesis of ET remained unknown until 2005, when activating mutations in the JAK2 tyrosine kinase (JAK2V617F) were identified in a significant proportion of patients with ET, polycythemia vera (PV) and primary myelofibrosis (PMF). In addition, subsequent studies have identified gain-of-function mutations in the thrombopoietin receptor (MPL) in a subset of patients with JAK2V617F-negative ET, suggesting that JAK2 activation by distinct mechanisms contributes to the pathogenesis of ET. Despite these important observations, important questions remain regarding the role of JAK2/MPL mutations in ET pathogenesis, the etiology of JAK2/MPL negative ET, the factors that distinguish ET from other MPNs with the JAK2V617F mutation, and the role of JAK2-targeted therapies for the treatment of these MPNs.
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PMID:New advances in the pathogenesis and therapy of essential thrombocythemia. 1907 62

Both the 2001 World Health Organisation (WHO) classification of haematopoietic neoplasms and the 2008 WHO classification revision include a distinctive diagnostic category, refractory anaemia with ring sideroblasts and thrombocytosis (RARS-T), to describe those rare patients who have both >or=15% ring sideroblasts and a sustained elevated platelet count. Recently, it has become clear that patients meeting WHO criteria for RARS-T have clonal JAK2(V617F) and MPL(W515) mutations at a similar rate to essential thrombocythaemia (ET). Given that the provisional classification of RARS-T as a myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN) overlap syndrome, rather than as a form of MPN (i.e., ET), rests principally upon the presence of ring sideroblasts, which are a non-specific morphological finding, these new molecular results prompt reconsideration of the necessity for a distinctive RARS-T category. Here we review the historical developments that led up the definition of RARS-T as a disease entity, and we discuss conceptual understanding of RARS-T and arguments against continued use of RARS-T as a separate diagnostic category.
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PMID:Is refractory anaemia with ring sideroblasts and thrombocytosis (RARS-T) a necessary or useful diagnostic category? 1912 Mar 70

Therapeutically validated oncoproteins in myeloproliferative neoplasms (MPNs) include BCR-ABL in chronic myelogenous leukemia (CML) and a spectrum of PDGFRA/B mutant proteins that are products of intra- (eg, FIP1L1-PDGFRA) or interchromosomal (eg, ETV6-PDGFRB) gene fusions. Other MPN-relevant putative oncogenes that are awaiting therapeutic validation, include JAK2 and MPL mutations in polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF); KITD816V and other KIT mutations in systemic mastocytosis, and FGFR1 rearrangements associated with the 8p11 leukemia/lymphoma syndrome. The current review focuses on mutant molecules of interest in classic MPNs (ie, CML, PV, ET, and PMF) in the context of their value as drug targets.
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PMID:Oncogenic signals as treatment targets in classic myeloproliferative neoplasms. 1914 89

The activating W515L mutation in the thrombopoietin receptor (MPL) has been identified in primary myelofibrosis and essential thrombocythemia. MPL belongs to a subset of the cytokine receptor superfamily that requires the JAK2 kinase for signaling. We examined whether the ligand-independent MPL(W515L) mutant could signal intracellularly. Addition of the endoplasmic reticulum (ER) retention KDEL sequence to the receptor C terminus efficiently locked MPL(W515L) within its natural ER/Golgi maturation pathway. In contrast to cells expressing the parental MPL(W515L), MPL(W515L)-KDEL-expressing FDC-P1 cells were unable to grow autonomously and to produce tumors in nude mice. When observed, tumor nodules resulted from in vivo selection of cells leaking the receptor at their surface. JAK2 co-immunoprecipitated with MPL(W515L)-KDEL but was not phosphorylated. We generated disulfide-bonded MPL(W515L) homodimers by the S402C substitution, both in the normal and KDEL context. Unlike MPL(W515L)-KDEL, MPL(W515L-S402C)-KDEL signaled constitutively and exhibited cell surface localization. These data establish that MPL(W515L) with appended JAK2 matures through the ER/Golgi system in an inactive conformation and suggest that the MPL(W515L)/JAK2 complex requires membrane localization for JAK2 phosphorylation, resulting in autonomous receptor signaling.
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PMID:Ligand-independent thrombopoietin mutant receptor requires cell surface localization for endogenous activity. 1926 14

Somatic mutations in Janus kinase 2 (JAK2), including JAK2V617F, result in dysregulated JAK-signal transducer and activator transcription (STAT) signaling, which is implicated in myeloproliferative neoplasm (MPN) pathogenesis. CYT387 is an ATP-competitive small molecule that potently inhibits JAK1/JAK2 kinases (IC(50)=11 and 18 nM, respectively), with significantly less activity against other kinases, including JAK3 (IC(50)=155 nM). CYT387 inhibits growth of Ba/F3-JAK2V617F and human erythroleukemia (HEL) cells (IC(50) approximately 1500 nM) or Ba/F3-MPLW515L cells (IC(50)=200 nM), but has considerably less activity against BCR-ABL harboring K562 cells (IC=58 000 nM). Cell lines harboring mutated JAK2 alleles (CHRF-288-11 or Ba/F3-TEL-JAK2) were inhibited more potently than the corresponding pair harboring mutated JAK3 alleles (CMK or Ba/F3-TEL-JAK3), and STAT-5 phosphorylation was inhibited in HEL cells with an IC(50)=400 nM. Furthermore, CYT387 selectively suppressed the in vitro growth of erythroid colonies harboring JAK2V617F from polycythemia vera (PV) patients, an effect that was attenuated by exogenous erythropoietin. Overall, our data indicate that the JAK1/JAK2 selective inhibitor CYT387 has potential for efficacious treatment of MPN harboring mutated JAK2 and MPL alleles.
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PMID:CYT387, a selective JAK1/JAK2 inhibitor: in vitro assessment of kinase selectivity and preclinical studies using cell lines and primary cells from polycythemia vera patients. 1929 46


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