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)

Reciprocal translocations involving the long arm of chromosome 7 are relatively rare cytogenetic aberrations in myelodysplastic syndrome (MDS) and acute myeloblastic leukemia (AML). A 44-year-old woman was initially given a diagnosis of de novo AML M6A with a normal karyotype. After achieving complete remission, she received allogeneic bone marrow transplantation from an unrelated male donor. Seven months later, pancytopenia appeared with 14.8% myeloblasts and dysplastic changes of neutrophils and megakaryocytes in the bone marrow. Chromosome analysis revealed complex karyotypes, with add(7)(q22) and add(9)(q34) detected in all abnormal metaphase spreads; spectral karyotyping revealed these chromosomal aberrations to be derived from a reciprocal translocation t(7;9)(q22;q34). Fluorescence in situ hybridization analyses showed that D7S486 at 7q31 was translocated to the der(9)t(7;9), and that the ABL gene at 9q34 remained on the der(9)t(7;9). Because the same translocation reappeared and sustained for more than 8 months after second stem cell transplantation, we revised the diagnosis as therapy-related MDS after allogeneic transplantation. The t(7;9)(q22;q34) was supposed to have a crucial role in the pathogenesis of MDS. Considering two other such reported cases of AML, the t(7;9)(q22;q34) may be a novel recurrent translocation in myeloid malignancies.
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PMID:Translocation (7;9)(q22;q34) in therapy-related myelodysplastic syndrome after allogeneic bone marrow transplantation for acute myeloblastic leukemia. 1757 66

Extramedullary hematopoiesis (EMH) in the spleen is a characteristic feature of the chronic myeloproliferative disorders (CMPDs) and various other neoplastic or reactive myeloid conditions. However, the origin of these hematopoietic precursor cells and the molecular mechanisms underlying their development in the spleen is uncertain. The V617F mutation in the Janus Kinase 2 gene (JAK2(V617F)) was recently shown to be frequently and preferentially present in the peripheral blood and bone marrow cells of CMPD patients, and the resulting dysregulation of its downstream targets is important to CMPD pathogenesis. To determine the occurrence and potential role of JAK2(V617F) in splenic EMH cells, we studied splenectomy specimens from 47 patients with significant EMH. JAK2(V617F) was detected by real-time PCR melting curve analysis in 22 specimens, including 11/17 chronic idiopathic myelofibrosis, 7/7 polycythemia vera, 1/1 essential thrombocythemia, 1/3 CMPD unclassifiable, 1/5 chronic myelomonocytic leukemia, 0/5 chronic myelogenous leukemia, 1/3 myelodysplastic syndrome and 0/6 acute myeloblastic leukemia cases, whereas only the JAK2 wild-type allele was detected in the other 25. Nineteen of 20 cases with adequate bone marrow samples available for molecular examination demonstrated concordant JAK2 genotypes. Laser-capture microdissection was then used to enrich the EMH and non-EMH splenic cell fractions, confirming that the mutant alleles specifically originated from the EMH cells. Furthermore, megakaryocytes in the JAK2(V617F)-positive splenectomy specimens expressed higher levels of Bcl-xL, an antiapoptotic protein and downstream target of the JAK2/STAT5 pathway. Thus, JAK2(V617F) is frequently present in splenic EMH cells associated with CMPD, but it is rarely identified in splenic EMH cells associated with other myeloid disorders. Our results indicate that the precursor cells leading to extramedullary hematopoietic expansion in CMPD most likely originate from the transformed bone marrow clone. Also, dysregulation of downstream pathways such as Bcl-xL may be important to CMPD disease pathogenesis in the spleen.
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PMID:The role of Janus Kinase 2 V617F mutation in extramedullary hematopoiesis of the spleen in neoplastic myeloid disorders. 1764

Erlotinib, an inhibitor of the epidermal growth factor receptor (EGFR), induces differentiation, cell-cycle arrest, and apoptosis of EGFR-negative myeloblasts of patients with myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), as well as in EGFR-negative cell lines representing these diseases (P39, KG-1, and HL 60). This off-target effect can be explained by inhibitory effects on JAK2. Apoptosis induction coupled to mitochondrial membrane permeabilization occurred independently from phenotypic differentiation. In apoptosis-sensitive AML cells, erlotinib caused a rapid (within less than 1 hour) nucleocytoplasmic translocation of nucleophosmin-1 (NPM-1) and p14(ARF). Apoptosis-insensitive myeloblasts failed to manifest this translocation yet became sensitive to apoptosis induction by erlotinib when NPM-1 was depleted by RNA interference. Moreover, erlotinib reduced the growth of xenografted human AML cells in vivo. Erlotinib also killed CD34(+) bone marrow blasts from MDS and AML patients while sparing normal CD34(+) progenitors. This ex vivo therapeutic effect was once more associated with the nucleocytoplasmic translocation of NPM-1 and p14(ARF). One patient afflicted with both MDS and non-small cell lung cancer manifested hematologic improvement in response to erlotinib. In summary, we here provide novel evidence in vitro, ex vivo, and in vivo for the potential therapeutic efficacy of erlotinib in the treatment of high-risk MDS and AML.
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PMID:Erlotinib exhibits antineoplastic off-target effects in AML and MDS: a preclinical study. 1792 89

We applied single nucleotide polymorphism arrays (SNP-A) to study karyotypic abnormalities in patients with atypical myeloproliferative syndromes (MPD), including myeloproliferative/myelodysplastic syndrome overlap both positive and negative for the JAK2 V617F mutation and secondary acute myeloid leukemia (AML). In typical MPD cases (N = 8), which served as a control group, those with a homozygous V617F mutation showed clear uniparental disomy (UPD) of 9p using SNP-A. Consistent with possible genomic instability, in 19/30 MDS/MPD-U patients, we found additional lesions not identified by metaphase cytogenetics. In addition to UPD9p, we also have detected UPD affecting other chromosomes, including 1 (2/30), 11 (4/30), 12 (1/30) and 22 (1/30). Transformation to AML was observed in 8/30 patients. In 5 V617F+ patients who progressed to AML, we show that SNP-A can allow for the detection of two modes of transformation: leukemic blasts evolving from either a wild-type jak2 precursor carrying other acquired chromosomal defects, or from a V617F+ mutant progenitor characterized by UPD9p. SNP-A-based detection of cryptic lesions in MDS/MPD-U may help explain the clinical heterogeneity of this disorder.
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PMID:SNP array karyotyping allows for the detection of uniparental disomy and cryptic chromosomal abnormalities in MDS/MPD-U and MPD. 1803 Mar 53

The Philadelphia (Ph) chromosome, or t(9;22), is the hallmark of chronic myelogenous leukemia (CML). It results in juxtaposition of the 5' part of the BCR gene on chromosome 22 to the 3' part of the ABL1 gene (previously ABL) on chromosome 9. CML is clinically characterized by three distinct phases: chronic, accelerated, and blast phase. Blast crisis is characterized by the rapid expansion of a population of differentiation arrested blast cells (myeloid or lymphoid cells population), with secondary chromosomal abnormalities present. We report a case of myeloid blast crisis of CML resistant to imatinib mesylate and chemotherapy. By use of cytogenetic, fluorescence in situ hybridization, and comparative genomic hybridization methods, we identified a cluster of BCR-ABL amplification on inverted duplication of the Ph chromosome with t(3;21)(q26;q22) and increased genomic levels of the RUNX1 gene (previously AML1). The t(3;21)(q26;q22) is a recurrent chromosomal abnormality in some cases of CML blast phase and in treatment-related myelodysplastic syndrome and acute myeloid leukemia. Amplification or copy number increase of RUNX1 has been reported in childhood acute lymphoblastic leukemia. Our study indicated that the progenitor of CML was BCR-ABL dependent through the amplification of Ph chromosome as a mechanism of resistance to imatinib therapy. The coexistence of BCR-ABL and t(3;21)(q26;q22) with RUNX1 rearrangement might play a pivotal role in the CML blast transformation.
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PMID:Amplification of BCR-ABL and t(3;21) in a patient with blast crisis of chronic myelogenous leukemia. 1806 36

An increased platelet number in blood depends on a limited spectrum of causes, which aren't always simple to identify. Secondary thrombocytosis is a reactive process in relation with acute or chronic inflammatory diseases, or asplenia. The infrequent inherited thrombocytoses disorders are suspected when similar cases are observed in the same family. However, the most frequent causes of chronic thrombocytosis in adults are the so-called chronic myeloproliferative syndromes (chronic myelocytic leukaemia, polycythemia vera, primary myelofibrosis, essential thrombocytemia), and to a lesser extent, myelodysplastic syndromes. In the course of these disorders, thrombocytosis is often the first recognized abnormality. Chronic myelocytic leukaemia is easily diagnosed owing to the presence of either the Philadelphia chromosome or the BCR-ABL fusion gene product. The next step still relies upon a distinction according to the PVSG or the WHO criteria of Polycythemia Vera (PV) and Idiopathic myelo fibrosis (IMF) to finally confirm genuine Essential Thrombocythemia (ET). The recent description of the V617F mutation of JAK2 in 90% of PV patients, 43 to 67% with IMF and 50% of ET diagnosed according to either the PVSG or the WHO criteria is a definite characteristic of clonality now accessible in haematology practice. However, this mutation is neither specific nor constant in any of the Philadelphia negative myeloproliferative disorders, which outlines the importance of the WHO criteria of megakaryocytic abnormalities on bone marrow biopsy as the hallmark of Ph negative MPDs. The exclusion of PV and of IMF, including pre fibrotic and early fibrotic forms is still required for the diagnosis of "true" ET. Disease stratification and treatment strategy are targeted on the evaluation and prevention of vascular complications. Acute leukaemia or myelodysplasia, and other clonal progressions like myelofibrotic transformation, are infrequent and delayed events. However, according to the present data, the risk of fibrotic progression or of leukaemic transformation is not related to the mutation status of ET patients.
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PMID:[Essential thrombocythemia. Contribution of the V617F JAK2 mutation to the pathophysiology, diagnosis and outcome]. 1807 52

The differences in clinical features and prognosis between hypoplastic myelodysplastic syndrome (h-MDS) and normo-/hypercellular MDS (NH-MDS) remain unsettled. In this study, the characteristics of 37 h-MDS patients and 152 NH-MDS patients were compared. Peripheral-blood white blood cell counts and bone marrow blast percentage were lower in h-MDS patients than in NH-MDS patients (P=0.012 and 0.016, respectively). Refractory anemia (RA) was predominant (56.8%) in h-MDS, whereas RA with excess of blast (RAEB) was most common (44.7%) in NH-MDS. Chromosomal abnormalities -7/7q- occurred less frequently in h-MDS patients than in NH-MDS patients (0 vs 18.3%, P=0.022). There was no significant difference in the prevalence of mutations of RAS, AML1, JAK2, PTPN11, FLT3/ITD, and hypermethylation of SOCS1 and SHP1 between these two groups. International Prognostic Scoring System (IPSS) was ideal for predicting prognoses in h-MDS patients (P=0.002). In low- or intermediate-1 (Int-1)-risk MDS patients, h-MDS patients had a superior survival than NH-MDS patients (P=0.01). In conclusion, distinct from NH-MDS, h-MDS patients have different patterns of hemogram, distribution of French-American-British subtypes, cytogenetic changes and prognoses. IPSS is applicable in h-MDS as in NH-MDS. In patients with low- or Int-1-risk MDS, h-MDS patients have a better prognosis than NH-MDS patients.
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PMID:Comparison of hypoplastic myelodysplastic syndrome (MDS) with normo-/hypercellular MDS by International Prognostic Scoring System, cytogenetic and genetic studies. 1809 13

Acquired molecular abnormalities (mutations or chromosomal translocations) of the RUNX1 transcription factor gene are frequent in acute myeloblastic leukemias (AMLs) and in therapy-related myelodysplastic syndromes, but rarely in acute lymphoblastic leukemias (ALLs) and chronic myelogenous leukemias (CMLs). Among 18 BCR-ABL+ leukemias presenting acquired trisomy of chromosome 21, we report a high frequency (33%) of recurrent point mutations (4 in myeloid blast crisis [BC] CML and one in chronic phase CML) within the DNA-binding region of RUNX1. We did not found any mutation in de novo BCR-ABL+ ALLs or lymphoid BC CML. Emergence of the RUNX1 mutations was detected at diagnosis or before the acquisition of trisomy 21 during disease progression. In addition, we also report a high frequency of cryptic chromosomal RUNX1 translocation to a novel recently described gene partner, PRDM16 on chromosome 1p36, for 3 (21.4%) of 14 investigated patients: 2 myeloid BC CMLs and, for the first time, 1 therapy-related BCR-ABL+ ALL. Two patients presented both RUNX1 mutations and RUNX1-PRDM16 fusion. These events are associated with a short survival and support the concept of a cooperative effect of BCR-ABL with molecular RUNX1 abnormalities on the differentiation arrest phenotype observed during progression of CML and in BCR-ABL+ ALL.
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PMID:RUNX1 DNA-binding mutations and RUNX1-PRDM16 cryptic fusions in BCR-ABL+ leukemias are frequently associated with secondary trisomy 21 and may contribute to clonal evolution and imatinib resistance. 1820 28

Histomorphological evaluation of bone marrow trephines and smears represents the major approach to diagnose the chronic myeloproliferative diseases (CMPD) and the myelodysplastic syndromes (MDS). However, rising insights into molecular pathogenesis of human diseases strengthen the attempt of pathologists to define and to detect underlying defects beyond the microscope. Since discovery of the Philadelphia chromosome in chronic myeloid leukemia as the first specific molecular abnormality ever detected in a human neoplasia the gain of knowledge of molecular pathomechanisms in Philadelphia chromosome negative (Ph-) CMPD was rather sparse. A decisive breakthrough in Ph CMPD was the finding of JAK2 (V617F) derived from a somatic point mutation in the majority of patients with polycythemia vera (P.vera) and half of patients with essential thrombocythemia (ET) and primary myelofibrosis (PMF). It therefore can not be overestimated that detection of JAK2 (V617F) in a suspective myeloproliferation now enables a clearcut discrimination of a true Ph CMPD from a reactive state, e.g. P.vera from reactive erythrocytosis. Interestingly, a basic principle of molecular defects demonstrable in CMPD and related disorders seems to be the involvement of genes with kinase activities. Some of those genes will be discussed in more detail. In primary MDS, karyotyping via classical cytogenetics is the predominant molecular approach to estimate prognosis, e.g. -Y, del(5q) and del(20q) represent favourable anomalies. Indeed, in 5q- syndromes karyotyping enables definite subtyping and allows clinicians and patients to expect a good prognosis. Until now, dozens of molecular abnormalities such as mutations in AML1, FLT3 and Ras as well as epigenetic alterations of genes have been identified to various degrees in MDS subtypes. Some of them seem to be involved in disease initiation ("master event") and others might indicate disease progression. However, even though useful for further dissection of molecular pathomechanisms the majority of aberrations currently does not serve as potent markers in the daily routine. Nevertheless, in CMPD and MDS the importance of molecular analyses for diagnosis, estimation of prognosis, and disease monitoring will further increase in a foreseeable period of time.
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PMID:[Molecular diagnosis of chronic myeloproliferative diseases and myelodysplastic syndromes]. 1831 8

As JAK2 V617F, MPL W515L is a novel acquired mutation that induces constitutive cytokine-independent activation of the JAK-STAT pathway in myeloproliferative disorders (MPD). The discovery of this mutation provides a novel mechanism for activation of signal transduction in hematopoietic malignancies. To investigate its prevalence in Chinese patients with MPD, we introduced allele-specific PCR (AS-PCR) combined with sequence analysis to simultaneously screen MPL W515L and JAK2 V617F mutations in 190 MPD patients. MPL W515L mutation was found to be harbored in only one of 102 patients, who had essential thrombocythemia (ET, 1.0%) and was not detected in patients with polycythemia vera (PV), idiopathic myelofibrosis (IMF), and chronic myelogenous leukemia (CML). Sixty-eight BCR/ABL-negative MPD patients (46.3%) were found harboring JAK2 V617F mutation (PV, 62.5%; ET, 42.1%; IMF 38.1%). Furthermore, MPL W515L and JAK2 V617F mutations were not detected in patients of acute myeloid leukemia, acute lymphoblastic leukemia, myelodysplastic syndromes, and CML. It has been shown that MPL W515L mutations may contribute to the primary molecular pathogenesis of Chinese patients with ET.
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PMID:MPL W515L mutation in Chinese patients with myeloproliferative diseases. 1846 14


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