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)

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

Nonrandom gene rearrangements have been demonstrated in leukemic cells at diagnosis. These genetic abnormalities are associated with specific types, clinical characteristics, and prognosis of acute leukemia. Common fusion transcripts in childhood acute lymphoblastic leukemia (ALL) are TEL-AML1, E2A-PBX, MLL-AF4, and BCR-ABL (p190) and in acute nonlymphoblastic leukemia (ANLL) are AML-ETO, PML-RARA, and CBFB-MYH11. Reverse transcription-polymerase chain reaction (RT-PCR) for detection of each individual fusion transcript is impractical and time consuming. The purpose of this study was to develop simple RT-PCR methods to identify common fusion transcripts of newly diagnosed acute leukemia in children. Total RNA was extracted from bone marrow samples of children diagnosed with acute leukemia. Multiplex RT-PCR panel A (ALL) included primers for TEL-AML1, E2A-PBX, MLL-AF4, and BCR-ABL (p190) whereas panel B (ANLL) composed of primers for AML-ETO, PML-RARA, and CBFB-MYH11. Known leukemic cell lines were used to serve as positive controls. Eighty three children diagnosed with ALL (n = 63) and ANLL (n = 20) were included in this study. Fusion transcripts could be identified using multiplex RT-PCR panel A for ALL and panel B for ANLL in 26/83 (31.3%) cases. In ALL samples, we found TEL-AML1 = 16/63 (25.4%), E2A-PBX = 3/63 (4.8%), MLL-AF4 = 1/63 (1.6%), and BCR-ABL = 1/63 (1.6%). Four cases of AML1-ETO (20%) and one PML-RARA (5%) were found in ANLL samples. In conclusion, our simple multiplex RT-PCR for detection of fusion transcripts in childhood acute leukemia was found to be a rapid, accurate, and effective method.
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PMID:Simple multiplex RT-PCR for identifying common fusion transcripts in childhood acute leukemia. 1866 25

MicroRNAs (miRNAs) control the expression of protein-coding genes in normal hematopoietic cells and, consequently, aberrant expression may contribute to leukemogenesis. To identify miRNAs relevant to pediatric acute lymphoblastic leukemia (ALL), we cloned 105 known and 8 new miRNA genes expressed in patients' leukemia cells. Instead of known miRNA genes, new miRNA genes were not evolutionarily conserved. Quantification of 19 selected miRNA genes revealed an aberrant expression in ALL as compared with normal CD34+ cells (P <or= 0.02); both upregulated (14/19) and downregulated (5/19) expressions were observed. Eight miRNAs were differentially expressed between MLL and non-MLL precursor B-ALL cases (P<0.05). Most remarkably, miR-708 was 250- up to 6500-fold higher expressed in 57 TEL-AML1, BCR-ABL, E2A-PBX1, hyperdiploid and B-other cases than in 20 MLL-rearranged and 15 T-ALL cases (0.0001<P<0.01), whereas the expression of miR-196b was 500-fold higher in MLL-rearranged and 800-fold higher in 5 of 15 T-ALL cases as compared with the expression level in the remaining precursor B-ALL cases (P<0.001). The expression did not correlate with the maturation status of leukemia cells based on immunoglobulin and T-cell receptor rearrangements, immunophenotype or MLL-fusion partner. In conclusion, we identified new miRNA genes and showed that miRNA expression profiles are ALL subtype-specific rather than linked to the differentiation stadium associated with these subtypes.
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PMID:Identification of new microRNA genes and aberrant microRNA profiles in childhood acute lymphoblastic leukemia. 1892 41

Human ESCs provide an opportunity for modeling human-specific strategies to study the earliest events leading to normal hematopoietic specification versus leukemic transformation. Of interest, are the human childhood acute leukemias harboring specific fusion oncogenes such as MLL-AF4, TEL-AML1 or BCR-ABL wherein clinically significant manifestations arise in utero. The mechanisms of transformation are not amenable to analysis with patient samples and, many mouse models for pediatric leukemias have fallen short in illuminating the human disease because they do not recapitulate key aspects of the actual disease, suggesting that the mouse models are missing essential components of oncogenesis present in the human embryo. Prior to using hESCs as a tentative system for modeling leukemia, robust studies aimed at demonstrating their genetic stability are required; otherwise, cooperating mutations already present could prime hESCs susceptible to transformation. We performed an extensive molecular cytogenetic and cellular in vitro and in vivo analysis which reveals an overall genomic stability of HS181 and HS293 hESCs maintained long-term by mechanical dissociation in human feeders. Importantly, we show for the first time that the genetically stable HS181 hESC line differentiates into CD45+ hematopoietic cells and clonogenic hematopoietic progenitors. This data should encourage stem cell researchers to implement robust cytogenetic tools when assessing hESC genetic stability, in order to detect tiny but relevant biological functional or structural chromosome abnormalities and, paves the way for generating fusion oncogene-expressing transgenic hESCs as a human-specific system for studying the early in utero events leading to normal hematopoietic specification versus childhood leukemic transformation.
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PMID:Genetic stability of human embryonic stem cells: A first-step toward the development of potential hESC-based systems for modeling childhood leukemia. 1893 Mar 18

Childhood acute lymphoblastic leukaemia (ALL) is a heterogenous disease in which oncogene fusion transcripts are known to influence the biological behaviour of the different ALL subtypes. Screening for prognostically important transcripts is an important diagnostic step in treatment stratification and prognostication of affected patients. We describe a SYBR-Green real-time multiplex PCR assay to screen for transcripts TEL-AML1, E2A-PBX1, MLL-AF4, and the two breakpoints of BCR-ABL (p190 and p210). Validation of the assay was based on conventional karyotyping results. This new assay provides a rapid, sensitive, and accurate detection method for prognostically important transcripts in childhood ALL.
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PMID:Rapid detection of prognostically important childhood acute lymphoblastic leukemia chimeric transcripts using multiplex SYBR green real-time reverse transcription PCR. 1898 26

In Central America, nearly 70% of pediatric cancer is related to hemato-oncologic disorders, especially acute lymphoblastic leukemia (ALL). Preliminary studies have described a high incidence of childhood leukemia in these countries; however, no molecular analyses of these malignancies have yet been carried out. We studied diagnostic samples from 84 patients from the National Children's Hospital in San Jose, Costa Rica (65 precursor B-ALL, 5 T-cell ALL, and 14 acute myeloblastic leukemia). Our methodology included cytogenetic, fluorescent in situ hybridization, and polymerase chain reaction approaches. The observed rate of leukemia was 52.2 cases per million children per year. Twelve out of 65 (18.4%) precursor B-ALL tested positive for TEL-AML1 and 3 cases for BCR-ABL (4.6%). In addition, we detected 2 patients carrying an E2A-PBX1 transcript (3.1%) and 1 patient with an MLL-AF4 fusion gene (1.5%). None of the T-cell ALL cases were positive for either SIL-TAL1 or HOX11L2. Within 14 acute myeloblastic leukemia patients, we confirmed 2 cases with FLT3-internal tandem duplication+, 1 patient with AML1-ETO, and only 1 case carrying a PML-RARalpha rearrangement. The present study confirms the relatively high incidence of pediatric leukemia in Costa Rica and constitutes the first report regarding the incidence of the main molecular alterations of childhood leukemia in our region.
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PMID:Molecular and epidemiologic findings of childhood acute leukemia in Costa Rica. 1919

One of the highest incidences of acute lymphoblastic leukemia (ALL) in the world has been reported in Mexico City. In the current study (26 cases), the frequencies of the most frequent genetic rearrangements TEL-AML1, MLL/AF4, BCR-ABL (major and minor) in ALL in children from Mexico City were determined. For the ALL, the frequency of MLL/AF4 was 65.4%, for TEL-AML1 and that of BCR/ABL was 3.8%. Only 6 of the 17 children with the MLL/AF4 rearrangement were less than 26 months old. The frequency reported for MLL/AF4 in Mexican children with ALL is one of the highest worldwide. These findings could potentially explain the higher frequency of ALL with poor prognosis for children in Mexico City.
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PMID:Genetic rearrangement MLL/AF4 is most frequent in children with acute lymphoblastic leukemias in Mexico City. 1957 75

Mutational analysis of C-KIT, fms-like tyrosine kinase 3 (FLT3), and JAK2 genes was performed in 60 patients with core binding factor acute myeloid leukemia (CBF-AML). Patients reaching molecular remission had lower incidence of relapse and better overall survival (OS) than those not achieving molecular remission (p = 0.008 and 0.044, respectively). The overall incidence of C-KIT mutations was 33.3%, FLT3/internal tandem duplication (ITD) 6.6%, FLT3(D835) 10.0% and JAK2(V617F) mutations 3.3%. C-KIT mutations did not predict for clinical/molecular relapse (p = 0.33). OS of patients with C-KIT mutations was identical to patients without them when all patients with CBF-AML were analyzed together (p = 0.58). When AML1/ETO-positive patients were evaluated separately, OS in C-KIT-mutated patients was slightly inferior to unmutated ones (p = 0.14). Patients with CBF-AML with a mutated C-KIT gene were also more prone to extramedullary disease (p = 0.08). Of six patients harboring various FLT3(D835) mutations, four (66.7%) relapsed, whereas among 43 cases without these mutations, 16 relapses (37%) were observed (p = 0.08). Our results on minimal residual disease, C-KIT, and FLT3/ITDs are in line with previous studies. Surprisingly, a possible role for FLT3(D835) mutations was noted in addition. These results need validation in even larger patient cohorts than ours. For routine clinical practice, it may be meaningful to screen for C-KIT mutations in AML1/ETO-positive patients, as well as for FLT3(D835) mutations in CBF-AML.
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PMID:Monitoring of minimal residual disease in patients with core binding factor acute myeloid leukemia and the impact of C-KIT, FLT3, and JAK2 mutations on clinical outcome. 1967 79

Little was known about the mechanisms for myeloproliferative diseases (MPD) until 2005 when an activating mutation in the JAK2 tyrosine kinase (JAK2 V617F) was identified in >95% of patients with polycythemia vera (PV), and in a significant proportion of patients with essential thormbocythemia (ET) and primary myelofibrosis (PMF). Furthermore, activating abnormalities of some tyrosine kinases were identified in MPD and related diseases, suggesting that constitutive activation of the signaling pathway is a unifying feature of these diseases. On the other hand, the molecular mechanism of myelodysplastic syndromes (MDS) is still poorly understood. Recent study revealed that two types of AML1/RUNX1 mutants function via distinct molecular mechanisms to produce mutant-specific phenotypes of MDS. The mechanisms of MPD and MDS gradually become clear.
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PMID:[Molecular mechanisms in myeloproliferative diseases and myelodysplastic syndromes]. 1986 Jan 87

To develop effective cellular immunotherapy for hematopoietic malignancies, the tumor-associated antigens that are recognized by cytotoxic T lymphocytes (CTL) must be identified. Recently, various leukaemia-associated antigens that are recognized by CTL in the context of HLA class I molecules have been identified. These include fusion gene products such as BCR-ABL and ETV6-AML1, proteinase 3, WT1, human telomerase reverse transcriptase, cyclophilin B, and PRAME. In addition, various target antigens associated with other hematopoietic malignancies have been also identified. On the basis of these findings, various clinical trials of immunotherapy for hematological malignancies, including peptide vaccination, dendritic cell therapy, adoptive transfer of CTL, T-cell receptor gene therapy have been ongoing. Here, the current status and future feasibility of cellular immunotherapy for leukemia are discussed.
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PMID:[Immunotherapy and cell therapy for myeloid leukemia]. 1986 Jan 94


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