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)

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

In acute lymphoblastic leukemia, besides age and white cell count at diagnosis, the cytogenetic abnormalities t(9;22)/BCR-ABL and t(4;11)/MLL-AF4 are important prognostic markers and are often included in the treatment stratification of patients with adult acute lymphoblastic leukemia. Deletions in 9p are seen in about 9% of cases of adult acute lymphoblastic leukemia, but their prognostic impact has been controversial. Cytogenetic data from 381 patients diagnosed with B-precursor acute lymphoblastic leukemia were reviewed. Chromosomal analysis was successful in 240 cases. Of these cases, 18 (8%) had abnormalities in 9p and they were compared with patients with normal karyotypes and patients with t(9;22)/BCR-ABL. Patients with abnormalities of chromosome 9 showed significantly shorter overall survival compared with patients with normal karyotypes. In fact, overall survival was similar to that in the poor prognosis t(9;22)/BCR-ABL-positive group. Our data suggest that chromosomal abnormalities involving 9p may have a significant negative impact on survival in adult B-precursor acute lymphoblastic leukemia.
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PMID:An investigation into whether deletions in 9p reflect prognosis in adult precursor B-cell acute lymphoblastic leukemia: a multi-center study of 381 patients. 1872 22

Although c-Abl and D40 proteins are localized predominantly in nucleus, they are involved in different cellular processes. c-Abl is a tyrosine-kinase that takes part in protein phosphorylation on tyrosine. Recently D40 has been identified as a component of outer kinetochore complex. Despite of functional differences between c-Abl and D40 proteins, they have some similarities. First, high expression levels of c-Abl and D40 were observed not only in proliferating somatic cells, such as tumors, but also in healthy human testis. The increased expression levels of c-Abl and D40 protein in spermatocytes and acrosome of spermatids indicate their role in meiosis and spermatogenesis. Second, both proteins interact with specific regions of chromatin and are involved in the regulation of cell growth and division. Third, ABL and D40 (AF15q14) genes are involved in chromosomal translocations that subsequently form chimeric oncoproteins BCR-ABL, TEL-ABL and MLL-AF15q14 in human leukaemia. Finally, both proteins interact with the tumor suppressor pRb protein and subsequently can lead to regulation of the cell proliferation. The possible regulatory pathways that are controlled by c-Abl and D40 proteins are described here in details.
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PMID:[The involvement of c-Abl and D40 (AF15q14/CASC5) proteins in the regulation of cell proliferation and cancer]. 1877 Nov 74

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

MLL translocations in adult B-cell precursor (BCP) acute lymphoblastic leukemia (ALL) are largely restricted to the immature CD10(-) immunophenotypes. MLL-AF4 is known to be the most frequent fusion transcript, but the exact frequencies of MLL aberrations in CD10(-) adult BCP-ALL are unknown. We present a genetic characterization of 184 BCR-ABL(-) CD10(-) adult ALL cases (156 cyIg(-), 28 cyIg(+)) diagnosed between 2001 and 2007 at the central diagnostic laboratory of the GMALL study group. Patient samples were investigated by RT-PCR for MLL-AF4, MLL-ENL, and MLL-AF9 and by long-distance inverse polymerase chain reaction, thus also allowing the identification of unknown MLL fusion partners at the genomic level. MLL-AF4 was detected in 101 (54.9%) and MLL-ENL in 11 (6.0%) cases. In addition, rare MLL fusion genes were found: 2 MLL-TET1 cases, not previously reported in ALL, 1 MLL-AF9, 1 MLL-PTD, a novel MLL-ACTN4, and an MLL-11q23 fusion. Chromosomal breakpoints were determined in all 118 positive cases, revealing 2 major breakpoint cluster regions in the MLL gene. Characteristic features of MLL(+) patients were significantly lower CD10 expression, expression of the NG2 antigen, a higher white blood count at diagnosis, and female sex. Proposals are made for diagnostic assessment.
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PMID:The MLL recombinome of adult CD10-negative B-cell precursor acute lymphoblastic leukemia: results from the GMALL study group. 1914 82

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

Between 2000 and 2006, 85 adult BCR-ABL negative acute lymphoblastic leukaemia (ALL) patients between 18 and 60 years of age were treated using a modified paediatric regimen, which included high doses of asparaginase delivered weekly for 30 weeks during intensification. The complete response rate with induction therapy was 89%, and decreased with increasing age, mainly due to higher induction mortality. All post-induction treatments were delivered on an outpatient basis. The most common complications during intensification were infections (47%), osteonecrosis (32%), venous thromboembolism (23%) and neuropathy (22%). At a median follow-up of 4 years, the 5-year overall survival (OS) and relapse-free survival (RFS) were 63% and 71%, respectively. Significant adverse predictors for OS were age >35 years, high white blood cell count, MLL rearrangement, allogeneic stem cell transplantation in first complete remission and <80% of the planned asparaginase dose delivered during intensification. Patients aged < or = 35 years had a 3 year OS of 83%, as compared to 52% for patients aged >35 years. We conclude that the administration of this paediatric regimen is feasible and has considerable activity in adult ALL, particularly in younger patients. Effective delivery of asparaginase dosing appears to be important in achieving an optimal antileukaemic effect.
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PMID:Treatment of adults with BCR-ABL negative acute lymphoblastic leukaemia with a modified paediatric regimen. 1943 71

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


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