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)

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

The first formal classification of chronic myeloid neoplasms is credited to William Dameshek, who in 1951 described the concept of "myeloproliferative disorders (MPD)" by grouping together chronic myelogenous leukemia, polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). The 2001 World Health Organization (WHO) classification of myeloid malignancies included these MPDs under the broader category of chronic myeloproliferative diseases (CMPD), which also included chronic neutrophilic leukemia, chronic eosinophilic leukemia/hypereosinophilic syndrome (CEL/HES), and "CMPD, unclassifiable." The revised 2008 WHO classification system featured the following changes: 1) the term "CMPD" was replaced by "myeloproliferative neoplasm (MPN)," 2) mast cell disease was formally included under the category of MPN, and 3) the subcategory of CEL/HES was reorganized into "CEL not otherwise specified (CEL-NOS)" and "myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB, and FGFR1"; CEL-NOS remained a subcategory of "MPN," whereas the latter neoplasms were now assigned a new category of their own. Furthermore, diagnostic criteria for PV, ET, and PMF were revised by incorporating recently described molecular markers (eg, JAK2 and MPL mutations) as well as underscoring the role of histology in differentiating reactive from clonal myeloproliferations. As a result, red cell mass measurement is no longer necessary for the diagnosis of PV, and ET can now be diagnosed at a lower platelet count threshold. The revised WHO document continues to promote the recognition of histologic categories as a necessary first step toward the genetic characterization of myeloid malignancies.
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PMID:The 2008 World Health Organization classification system for myeloproliferative neoplasms: order out of chaos. 1947 96

Myeloid leukemia in this series corresponds to the myeloid neoplasms of the 4th WHO classification of pathology and genetics of tumor of haematopoietic and lymphoid tissue. The myeloid neoplasms are composed of six categories, which are 1) myeloproliferative neoplasms (MPN), a new category of 2) myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB or FGFR1, 3) myelodysplastic syndrome (MDS)/MPN, 4) MDS, 5) acute myeloid leukemia (AML) and related precursor neoplasms, and 6) acute leukemias of ambiguous lineage. In MPNs without chronic myelogenous leukemia, the genetic marker of JAK2 V617F is added to the diagnostic criteria for polycythemia vera, essential thrombocythemia and primary myelofibrosis. MDS has the new subtype of refractory cytopenia with unilineage dysplasia composed of refractory anemia, refractory neutropenia and refractory thrombocytopenia. AML with t(9; 11) (p22;q23); MLLT3-MLL, AML with t(6;9) (p23; q34); DEK-NUP214, AML with inv(3) (q21q26.2) or t(3; 3) (q21 ; q26.2); RPN1-EVI1 and AML (megakaryoblastic) with t(1; 22) (p13; q13); RBM15-MKL1 are added to the subtype of AML with recurrent genetic abnormalities, and AML with gene mutations of NPM1 and CEBPA are also added as provisional entities of it. The myeloid neoplasms of the 4th WHO classification are comprehensive and seem to be dynamic by incorporating the results of leukemia researches.
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PMID:[Classification of myeloid leukemias]. 1986 Jan 79

Myeloproliferative neoplasms (MPNs) and related chronic disorders constitute a subgroup of myeloid malignancies which are defined according to clinical, morphological and molecular features by the actual World Health Organization classification of tumors of the haematopietic system. Screening procedures for a BCR-ABL fusion gene, JAK2, thrombopoietin receptor and KIT mutations are formally included in the diagnostic approach. Myelodysplastic/MPN overlap syndromes include rare entities such as refractory anemia with ringed sideroblasts characterized by a high proportion of JAK2V617F mutated cases. The paradigm of targeted treatment of chronic myeloid leukemia with imatinib has now been extended to eosinophilia-associated myeloid neoplasms with PDGFRA, PDGFRB or FGFR1 gene mutations. Pegylated interferon-alpha has convincingly been proved to reduce the JAK2 allele burden. JAK2 inhibitor drugs are currently being tested in clinical trials. The development of pathogenesis-targeted diagnostic and therapeutic approaches to the various MPNs will continue in the future.
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PMID:[Chronic myeloid neoplasms. Diagnostic criteria and current therapeutic concepts]. 2007 59

The myeloproliferative neoplasms (MPNs) were first recognized by William Dameshek in 1951. The classic MPNs were polycythemia vera (PV), essential thrombocythemia (ET), primary myelofibrosis (PMF) and chronic myelogenous leukemia. They were originally grouped together based on their shared phenotype of myeloproliferation. Since then, important discoveries have been made, identifying a central role of protein tyrosine kinases in the pathogenesis of these disorders. As such, the 2008 WHO diagnostic classification for myeloproliferative neoplasms has incorporated molecular markers with histologic, clinical and laboratory information into the diagnostic algorithms for the MPNs. Important changes include (1) the change of nomenclature of myeloproliferative disorder to myeloproliferative neoplasm emphasizing the clonal nature of these disorders; (2) the classification of mast cell disease as an MPN; (3) the reorganization of the eosinophilic disorders into a molecularly defined category of PDGFRA, PDGFRB and FGFR1-associated myeloid and lymphoid neoplasms with eosinophilia and chronic eosinophilic leukemia, not otherwise specified; and (4) refinement of the diagnostic criteria for PV, ET and PMF incorporating recently described molecular markers, JAK2V617F, JAK2 exon 12 mutations and MPL mutations. This review focuses upon the important changes of the 2008 WHO diagnostic criteria for MPNs.
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PMID:Classification and diagnosis of myeloproliferative neoplasms according to the 2008 World Health Organization criteria. 2019 32

The fourth edition of the World Health Organization (WHO) classification of myeloid neoplasms refined the criteria for some previously described myeloid neoplasms and recognized several new entities based on recent elucidation of molecular pathogenesis, identification of new diagnostic and prognostic markers, and progress in clinical management. Protein tyrosine kinase abnormalities, including translocations or mutations involving ABL1, JAK2, MPL, KIT, PDGFRA, PDGFRB, and FGFR1, have been used as the basis for classifying myeloproliferative neoplasms (MPN). Two new entities - refractory cytopenia with unilineage dysplasia and refractory cytopenia of childhood have been added to the group of myelodysplastic syndromes (MDS), and 'refractory anemia with excess blasts-1' has been redefined to emphasize the prognostic significance of increased blasts in the peripheral blood. A list of cytogenetic abnormalities has been introduced as presumptive evidence of MDS in cases with refractory cytopenia but without morphologic evidence of dysplasia. The subgroup 'acute myeloid leukemia (AML) with recurrent genetic abnormalities' has been expanded to include more molecular genetic aberrations. The entity 'AML with multilineage dysplasia' specified in the 2001 WHO classification has been renamed 'AML with myelodysplasia-related changes' to include not only cases with significant multilineage dysplasia but also patients with a history of MDS or myelodysplasia-related cytogenetic abnormalities. The term 'therapy-related myeloid neoplasms' is used to cover the spectrum of disorders previously known as t-AML, t-MDS, or t-MDS/MPN occurring as complications of cytotoxic chemotherapy and/or radiation therapy. In this review, we summarize many of these important changes and discuss some of the diagnostic challenges that remain.
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PMID:Recent advances in the diagnosis and classification of myeloid neoplasms--comments on the 2008 WHO classification. 2062 69

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

The introduction of JAK2 mutation testing has changed dramatically the diagnostic algorithms for myeloproliferative neoplasms (MPNs) but there is still a place for conventional cytogenetic analysis in the initial work-up of MPN cases, particularly as this group of myeloid disorders has been expanded to include chronic eosinophilic leukaemia and myeloid neoplasms with abnormalities of the PDGFRA, PDGFRB, and FGFR1 genes. Mastocytosis is also included under the umbrella of MPN but the cytogenetic abnormalities observed usually reflect any associated clonal haematological non-mast cell lineage disease.
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PMID:Cytogenetics of myeloproliferative neoplasms. 2143 36

Tyrosine kinase fusion genes represent an important class of oncogenes associated with leukaemia and solid tumours. They are produced by translocations and other chromosomal rearrangements of a subset of tyrosine kinase genes, including ABL, PDGFRA, PDGFRB, FGFR1, SYK, RET, JAK2 and ALK. Based on recent findings, this review discusses the common mechanisms of activation of these fusion genes. Enforced oligomerization and inactivation of inhibitory domains are the two key processes that switch on the kinase domain. Activated tyrosine kinase fusions then signal via an array of transduction cascades, which are largely shared. In addition, the fusion partner provides a scaffold for the recruitment of proteins that contribute to signalling, protein stability, cellular localization and oligomerization. The expression level of the fusion protein is another critical parameter. Its transcription is controlled by the partner gene promoter, while translation may be regulated by miRNA. Several mechanisms also prevent the degradation of the oncoprotein by proteasomes and lysosomes, leading to its accumulation in cells. The selective inhibition of the tyrosine kinase activity by adenosine-5'-triphosphate competitors, such as imatinib, is a major therapeutic success. Imatinib induces remission in leukaemia patients that are positive for BCR-ABL or PDGFR fusions. Recently, crizotinib produced promising results in a subtype of lung cancers with ALK fusion. However, resistance was reported in both cases, partially due to mutations. To tackle this problem, additional levels of therapeutic interventions are suggested by the complex mechanisms of fusion tyrosine kinase activation. New approaches include allosteric inhibition and interfering with oligomerization or chaperones.
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PMID:Tyrosine kinase gene fusions in cancer: translating mechanisms into targeted therapies. 2185 43

As well as playing vital roles in main cellular processes, such as abnormal proliferation, differentiation, survival, apoptosis, and a lot of tyrosine kinases (TK) are involved in oncogenesis. TK or components of their signal pathways have been found abnormal in many hematological malignancies. Therefore, tyrosine kinase inhibitors (TKI) have been provided a great deal of enthusiasm for development of therapy in myeloproliferative neoplasms (MPN). Representativity, the treatment of chronic myelogenous leukemia (CML) was revolutionary for the design of imatinib mesylate (IM), which is a BCR/ABL TKI. Subsequently, because of need for the resistance or intolerance, novel agents are being explored and imatinib has now been extended to eosinophilia-associated myeloid neoplasms with PDGFRA, PDGFRB or FGFR1 gene mutations. Recently, JAK2 inhibitor drugs are currently being tested in clinical trials. Here, the current review mainly focuses on the role of TK in classic MPN including CML, polycythemia vera (PV), primary myelofibrosis (PMF), essential thrombocythemia (ET), and advances of targeting these abnormalities with small molecule inhibitors.
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PMID:Application of tyrosine kinase inhibitors as a promising targeting treatment for myeloproliferative neoplasms --- review. 2186 45


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