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)

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

Chronic myeloid neoplasm with eosinophilia and abnormalities of platelet-derived growth factor receptor alpha (PDGFRA), referred to until 2008 as chronic eosinophilic leukemia, is distinguished from hypereosinophilic syndrome (HES), if accompanied by genetic abnormalities that enable to determine eosinophil clonality. Typically, HES has a benign course and glucocorticosteroids suffice to achieve remission. In chronic myeloid neoplasm with eosinophilia and abnormalities of PDGFRA the FIP1L1-PDGFRA fusion gene can be detected. Its product is a protein showing tyrosine kinase activity leading to malignant proliferation of eosinophil precursors. Differential diagnosis of HES is often difficult because hypereosinophilia may also be reactive and may occur in many nonhematological as well as hematological disorders. Thus, reverse-transcription polymerase chain reaction (RT-PCR)is indicated in all patients with HES in order to detect the FIP1L1-PDGFRA transcript. Traditional treatment of chronic myeloid neoplasm with cytostatic drugs results in a short-term and transient remission or stabilization of the disease. We present the case of a 52-year-old patient with chronic myeloid neoplasm with eosinophilia and abnormalities of PDGFRA, in whom acceleration occurred after a year of cytostatic therapy with hydroxyurea and was successfully treated with imatinib. It was impossible to unequivocally determine the type of bone marrow disease based on histologic criteria, and a wide spectrum of molecular tests differentiating the type of myeloid proliferation were necessary to establish the diagnosis. RT-PCR did not reveal BCR-ABL or JAK2 V617F mutation. Further molecular testing showed rearrangement involving the FIP1L1 gene, thus enabling implementation of targeted therapy.
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PMID:A diagnostically difficult case of chronic myeloid neoplasm with eosinophilia and abnormalities of PDGFRA effectively treated with imatinib in accelerated phase: case report. 2001 Apr 73

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 ETV6/ABL1 (TEL/ABL) fusion gene is a rare aberration in malignant disorders. Only 19 cases of ETV6/ABL1-positive hematological malignancy have been published, diagnosed with chronic myeloid leukemia, other types of chronic myeloproliferative neoplasm, acute myeloid leukemia or acute lymphoblastic leukemia (ALL). This study reports three new cases (aged 8 months, 5 years, and 33 years) of ALL with the ETV6/ABL1 fusion found by screening 392 newly diagnosed ALL patients (335 children and 57 adults). A thorough review of the literature and an analysis of all published data, including the three new cases, suggest poor prognosis of ETV6/ABL1-positive acute leukemias. The course of the disease in the two pediatric patients is characterized by minimal residual disease monitoring, using quantification of both the ETV6/ABL1 transcript and immunoreceptor gene rearrangements. Eosinophilia could not be confirmed as a hallmark of the ETV6/ABL1-positive disease. Studies of neonatal blood spots demonstrated that, in the child diagnosed at five years, the ETV6/ABL1 fusion initiating the ALL originated prenatally.
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PMID:Acute leukemias with ETV6/ABL1 (TEL/ABL) fusion: poor prognosis and prenatal origin. 2058 32

Myeloproliferation with prominent eosinophilia is associated with rearrangements of PDGFR-A or -B. The most common rearrangement is FIP1L1-PDGFRA (FP). The majority of patients with PDGFR-rearranged myeloproliferation respond to treatment with imatinib. In contrast to BCR-ABL-positive chronic myelogenous leukemia, only few cases of imatinib resistance and mutations of the FP kinase domain have been described so far. We hypothesized that the number of critical residues mediating imatinib resistance in FP in contrast to BCR-ABL might be limited. We performed an established systematic and comprehensive in vitro resistance screen to determine the pattern and frequency of possible TKI resistance mutations in FP. We identified 27 different FP kinase domain mutations including 25 novel variants, which attenuated response to imatinib, nilotinib or sorafenib. However, the majority of these exchanges did not confer complete inhibitor resistance. At clinically achievable drug concentrations, FP/T674I predominated with imatinib, whereas with nilotinib and sorafenib, FP/D842V and the compound mutation T674I+T874I became prevalent. Our results suggest that the PDGFR kinase domain contains a limited number of residues where exchanges critically interfere with binding of and inhibition by available PDGFR kinase inhibitors at achievable concentrations, which might explain the low frequency of imatinib resistance in this patient population. In addition, these findings would help to select the appropriate second-line drug in cases of imatinib-resistant disease and may be translated to other neoplasms driven by activated forms of PDGFR-A or -B.
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PMID:The low frequency of clinical resistance to PDGFR inhibitors in myeloid neoplasms with abnormalities of PDGFRA might be related to the limited repertoire of possible PDGFRA kinase domain mutations in vitro. 2097 53

The paper discusses the new 2008 WHO classification of myeloproliferative neoplasms (MPN) and compares it with its previous 2001 edition. The introduction of the last version of the WHO classification into clinical practice has been due to new molecular biological and histological evidence in patients with MPN. The classification contains substantial alterations made in a number of nosological entities and the new diagnostic marker for MPN - JAK2 gene mutation being proposed. Mastocytosis-specific c-KIT anomaly is identified. A new form of hematopoietic system tumors, such as myeloid and lymphoid neoplasias with eosinophilia and mutations of the PDGFR A and B and FGFR1 genes, is singled out and characterized. New differential diagnostic parameters of a histological study of bone marrow trepans in MPN are proposed.
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PMID:[Current diagnosis of myeloproliferative neoplasms (2008 WHO classification)]. 2143 18

Imatinib-resistant tyrosine kinase (TK) fusions involving FGFR1, JAK2, or FLT3 are rare but recurrent in patients with eosinophilia-associated neoplasms. We report here 2 male patients with ETV6-FLT3(+) myeloid/lymphoid neoplasms with eosinophilia who were treated with the multitargeted TK inhibitors sunitinib and sorafenib. Patient 1 achieved rapid complete hematologic response and complete cytogenetic response after 3 months of taking sunitinib. A secondary blast phase caused by clonal evolution was diagnosed after 6 months. He achieved a second complete hematologic response after taking sorafenib but relapsed 2 months later. An N841K point mutation within the TK domain of FLT3, previously reported in acute myeloid leukemia and potentially conferring resistance to sorafenib, was subsequently identified. Patient 2 was heavily pretreated according to the initial diagnosis of T-lymphoblastic lymphoma and died in sunitinib-induced pancytopenia. This report highlights the importance of a careful diagnostic workup for eosinophilia-associated neoplasms to evaluate the possibility of TK inhibitor therapy.
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PMID:Response of ETV6-FLT3-positive myeloid/lymphoid neoplasm with eosinophilia to inhibitors of FMS-like tyrosine kinase 3. 2170 1

The t(8;21)(q22;q22) is the most common translocation in acute myeloid leukemia (AML). We describe the clinicopathologic and cytogenetic profile of 117 patients with t(8;21) AML. There were 76 males and 88 adults. The median age was 26 years. Most patients (80%) had AML M2. Dysplasia was present in 68% of patients and eosinophilia in 18%. Eight patients had fewer than 20% blasts. Additional chromosomal aberrations were seen in 103 patients (88%) with loss of a sex chromosome (LSC) in 78 patients (66%) and deletion 9q in 21 (18%). The other recurrent abnormalities were trisomies 4, 8 and 15, monosomy 17 and deletion 7q (less than 5% each). Three- or four-way variant t(8;21) were seen in 6% of patients and 3% had tetraploidy. Aberrant expression of CD19 was seen in 54% of patients. FLT3 mutations were seen in 7.5% of patients (3/40) and c-KIT mutations in 6.6% (2/30). None had NPM1 or JAK2 V617F mutations. One patient had a granulocytic sarcoma. Complete remission was achieved in 96% of the 26 newly diagnosed patients after first induction. The median follow-up was 25 months (range 4-68). The overall survival was 69% at 31 months.
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PMID:Cytogenetic analysis of acute myeloid leukemia with t(8;21) from a tertiary care center in India with correlation between clinicopathologic characteristics and molecular analysis. 2174 4

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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