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)

It has recently been shown that the t(12;21)(p13;q22) translocation fuses two genes, TEL on chromosome 12 and AML1 on chromosome 21. We have evaluated the frequency of this newly described translocation in acute lymphoblastic leukemia (ALL), and the feasibility of minimal residual disease (MRD) monitoring by polymerase chain reaction (PCR) amplification of TEL-AML1 transcripts. Thirty-nine adult- and 45 childhood-ALLs consecutively diagnosed in a single center were included in this study. TEL-AML1 fusion transcripts were searched for in the 39 adult- and 45 childhood-ALLs for which material was available. BCR-ABL, E2A-PBX1, and MLL-AF4 transcripts were also studied by PCR in these cases. TEL-AML1 transcripts were found in 8 out of 35 (23%) childhood B-cell precursor ALLs (BCP-ALLs). TEL-AML1 transcripts were detected in only 1 of 31 adult BCP-ALLs (P = .04, Fisher's exact test). Nevertheless, in this adult case, TEL-AML1 transcripts were found at a low level in 2 of 3 different samples. BCR-ABL, E2A-PBX1, and MLL-AF4 transcripts were found in 12, 3, and 1 cases of 31 adult BCP-ALLs, and in 1, 2, and 1 cases of 35 childhood BCP-ALLs, respectively. TEL-AML1 transcripts were never found associated with any other fusion transcripts. Taken together, the four types of chimeric transcripts were detected in 12 of 35 (34%) childhood BCP-ALL cases. No TEL-AML1 transcripts were detected in 11 T-cell ALLs (4 adults and 5 children), nor in 2 B-cell (slg+) ALLs. MRD was evaluated in 21 samples collected in 9 TEL-AML1+ childhood BCP-ALL cases during therapy (median follow-up = 200 days). Of 8 patients evaluated after induction therapy, 4 showed detectable but low levels of MRD. Of 7 patients serially evaluated, only one showed persistence of detectable MRD. This study shows that TEL-AML1 transcripts are frequently detected in pediatric BCP-ALLs and that these transcripts are molecular targets that will simplify the strategy of MRD monitoring in childhood BCP-ALL.
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PMID:TEL-AML1 fusion RNA as a new target to detect minimal residual disease in pediatric B-cell precursor acute lymphoblastic leukemia. 870 88

We used reverse transcriptase polymerase chain reaction (RT-PCR) assays to examine primary leukemic cells in on-study diagnostic bone marrow specimens from 642 children with newly diagnosed acute lymphoblastic leukemia (ALL) for the expression of MLL-AF4, E2A-PBX1, and BCR-ABL fusion transcripts. All PCR assays were performed centrally in the Children's Cancer Group ALL Biology Reference Laboratory. MLL-AF4 transcript was found in only 0.7% of the study population which excluded infants. E2A-PBX1 transcript was found in 2.5% of the study population and 3.3% of B-precursor cases. Expression was associated with massive hepatomegaly. BCR-ABL transcript was found in 2.3% of cases and correlated with older age, induction failure, and inferior event-free survival (EFS). RT-PCR assays allow rapid identification of patients with MLL-AF4 and BCR-ABL positive ALL. These patients have a poor outcome with contemporary therapy and rapid identification facilitates timely allocation to innovative treatment programs.
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PMID:Expression of BCR-ABL, E2A-PBX1, and MLL-AF4 fusion transcripts in newly diagnosed children with acute lymphoblastic leukemia: a Children's Cancer Group initiative. 925 Jul 88

The t(12:21) translocation fuses the TEL and AML1 genes and has been found in up to 28% of paediatric B-cell precursor acute lymphoblastic leukaemias (BCP-ALL). The AML1 gene is a transcription factor which regulates expression of several myeloid differentiation associated genes. A molecular analysis of TEL-AML1, E2A-PBX1, MLL-AF4, BCR-ABL expression and an immunophenotypic study of CD13/CD33 myeloid antigen expression have been performed prospectively on tumour cells from 96 paediatric BCP-ALL patients. Percentages of CD13 or CD33 expressing leukaemic cells were found to be higher in TEL-AML1 positive cases (n = 22) than in TEL-AML1 negative (n = 74) cases (P<0.001). In 22/96 cases (23%) >10% of neoplastic cells were found to express at least one of the two markers. In 14 of these cases (63%), TEL-AML1 expression was detected, whereas t(4;11), t(11;19) and t(9;22) translocations were found by molecular methods in only three cases (14%). In four cases (18%) no molecular marker was found. These data show that TEL-AML1 expression is significantly associated with myeloid antigen expression by leukaemic cells and suggests that the prognostic significance of myeloid antigen expression in paediatric ALLs should be re-evaluated in the light of molecular cytogenetic markers.
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PMID:The majority of myeloid-antigen-positive (My+) childhood B-cell precursor acute lymphoblastic leukaemias express TEL-AML1 fusion transcripts. 935 9

A large number of continuous human leukemia cell lines have been established over the last three decades. Clearly, leukemia cell lines have become important research tools. Here, we have summarized the immunological, molecular and standard cytogenetic features of a panel of well characterized B cell precursor (BCP)-leukemia cell lines which were derived from patients with acute lymphoblastic/undifferentiated leukemia (ALL/AUL) or chronic myeloid leukemia (CML) in blast crisis. Following the recently proposed immunological EGIL classification, we assigned our panel of 27 BCP-cell lines to one of the following categories: B-I pro-B cell line; B-II common-B cell line; and B-III pre-B cell line. All cell lines express general B-lineage associated surface markers (HLA-DR, CD22, CD79a) being negative for surface immunoglobulin (Ig); the differences between the subgroups reside in expression of CD10 and cytoplasmic Ig. Several BCP-cell lines show the myelomonocytic cell-associated markers CD13 and/or CD33. These immunologically 'biphenotypic' BCP-cell lines are generally TdT+ CD10+ CD13+ CD19+ CD22+ CD34+ and carry the Philadelphia (Ph) translocation. The BCP-cell lines display surface receptors for interferon-gamma (CD119), interleukin-7 (CD127) and FLT-3 ligand (CD135). All BCP-cell lines examined have complex numerical and structural chromosomal alterations including translocations commonly seen in BCP-ALL such as t(4;11), t(9;22), t(11;19), t(12;21), and t(17;19) involving the fusion genes MLL-AF4, BCR-ABL, ENL-MLL, TEL/ETV6-AML1 and E2A-HLF, respectively. Besides the expected rearrangement of the Ig heavy chain receptor gene, several cell lines also have rearrangements of the T cell receptor genes beta, gamma or delta. While some BCP-cell lines express (aberrantly) myeloperoxidase at the mRNA level, most lines are negative in the immunological or cytochemical staining. Several large series documented the difficulty in establishing such BCP cell lines with success rates in the range of 10-20% (on average 15%). Still, since the establishment of the first bonafide BCP-cell line in 1974 (cell line REH), some 150 cell lines have been established of which, however, only a small percentage have been sufficiently well characterized and described. A higher success rate for immortalizing any given leukemia cell might depend on a closer emulation of the physiological in vivo microenvironment. The possibility to grow in vitro leukemia cells at will would represent ideal experimental systems permitting basic research and patient-specific investigations. In summary, the use of well-characterized BCP-cell lines provide unprecedented opportunities for studying a multitude of biological aspects related to normal and neoplastic B-lymphocytes.
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PMID:Establishment and characterization of human B cell precursor-leukemia cell lines. 968 Jan 6

Modern therapy for pediatric acute lymphoblastic leukemia (ALL) is based on the principle of risk stratification. One of the most important laboratory features used to accurately risk stratify patients is the presence of specific chromosomal translocation within the leukemic blasts. In this paper, we describe a multiplex reverse transcriptase-polymerase chain reaction (RT-PCR) assay for the accurate, sensitive, and rapid identification of chimeric transcripts encoded by the major risk-stratifying translocations of pediatric ALL. This assay will identify both the CML- and ALL-type BCR-ABL transcripts encoded by the t(9;22), all described variants of the E2A-PBX1 transcripts encoded by the t(1;19), the MLL-AF4 transcripts encoded by the t(4;11), and all variants of TEL-AML1 encoded by the t(12;21). In addition, we have developed a reverse dot-blot detection system as an alternative to traditional post-PCR Southern blot analysis. Application of this combined assay to the analysis of 70 leukemic samples and five cell lines resulted in a complete concordance between this multiplex assay and individual PCR reactions. The characteristics of the multiplex assay suggest that its application to routine clinical screening will significantly improve the ability of clinical laboratories to accurate risk stratify pediatric ALL patients.
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PMID:A multiplex RT-PCR assay for the detection of chimeric transcripts encoded by the risk-stratifying translocations of pediatric acute lymphoblastic leukemia. 984 30

Chromosomal rearrangements in childhood acute lymphoblastic leukemia (ALL) play an important role in the identification of clinical relevant subgroups. For rapid and easy detection of the clinically most important gene rearrangements, a nested multiplex reverse transcriptase polymerase chain reaction (multiplex PCR) was developed. This multiplex PCR enables the detection of M-BCR/ABL, m-BCR/ABL, TEL/ AML1, and MLL/AF4 fusion transcripts in one PCR reaction. However, the existence of splicing variants and different breakpoints on the DNA level hampers the discrimination of the rearrangements by their fragment size on an agarose gel. Therefore, one of the internal primers of each translocation (ABL-2, TEL-2, AF4-2) was labeled with a characteristic fluorescent dye, and an automatic fluorescence-based DNA fragment analysis was performed. The sensitivity of this multiplex PCR is in the same range as that of the corresponding single PCR reaction and allows a fast screening for the detection of therapy-relevant rearrangements, with a high turnover of samples.
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PMID:Multiplex PCR--a rapid screening method for detection of gene rearrangements in childhood acute lymphoblastic leukemia. 1034 46

Recent advances in cytogenetics and molecular genetics have made it possible to identify an array of genomic abnormalities with prognostic and therapeutic significance. Hyperdiploidy > 50 chromosomes and ETV6-CBFA2 fusions have been used to identify low-risk cases, and BCR-ABL and MLL-AF4 to define high-risk leukemias. Despite their clinical utility, the risk classification system based on these findings lack absolute precision and should be complemented with other variables, the most important of which is the early blast cell response to remission induction therapy. Studies of tumor suppressor genes and proto-oncogenes in the BCL2 family genes may unravel the mechanisms of leukemia cell progression and the development of drug resistance, leading to innovative therapies. As the cure rates for childhood acute lymphoblastic leukemia (ALL) approach 80%, precise methods of risk assessment are needed to permit better selection of treatment that is neither excessive nor inadequate for individual patients. Because one or more genetic abnormalities underlie every case of leukemia, a risk assignment system based on primary genetic abnormalities has great intuitive appeal. Even though over 90% of childhood ALL cases can be readily classified according to numerical or gross structural chromosomal abnormalities, molecular analyses are essential to identify therapeutically relevant, submicroscopic genetic lesions not visible by karyotyping. This review focuses mainly on recent advances in genetic studies that have contributed to therapeutic advances or that hold promise for the future.
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PMID:Genetic abnormalities and drug resistance in acute lymphoblastic leukemia. 1050 Aug 13

Prospective studies on the detection of minimal residual disease (MRD) in acute leukemia patients have shown that large-scale MRD studies are feasible and that clinically relevant MRD-based risk group classification can be achieved and can now be used for designing new treatment protocols. However, multicenter international treatment protocols with MRD-based stratification of treatment need careful standardization and quality control of the MRD techniques. This was the aim of the European BIOMED-1 Concerted Action 'Investigation of minimal residual disease in acute leukemia: international standardization and clinical evaluation' with participants of 14 laboratories in eight European countries (ES, NL, PT, IT, DE, FR, SE and AT). Standardization and quality control was performed for the three main types of MRD techniques, ie flow cytometric immunophenotyping, PCR analysis of antigen receptor genes, and RT-PCR analysis of well-defined chromosomal aberrations. This study focussed on the latter MRD technique. A total of nine well-defined chromosome aberrations with fusion gene transcripts were selected: t(1;19) with E2A-PBX1, t(4;11) with MLL-AF4, t(8;21) with AML1-ETO, t(9;22) with BCR-ABL p190 and BCR-ABL p210, t(12;21) with TEL-AML1, t(15;17) with PML-RARA, inv (16) with CBFB-MYH11, and microdeletion 1p32 with SIL-TAL1. PCR primers were designed according to predefined criteria for single PCR (external primers A <--> B) and nested PCR (internal primers C <--> D) as well as for 'shifted' PCR with a primer upstream (E5' primer) or downstream (E3' primer) of the external A <--> B primers. The 'shifted' E primers were designed for performing an independent PCR together with one of the internal primers for confirmation (or exclusion) of positive results. Various local RT and PCR protocols were compared and subsequently a common protocol was designed, tested and adapted, resulting in a standardized RT-PCR protocol. After initial testing (with adaptations whenever necessary) and approval by two or three laboratories, the primers were tested by all participating laboratories, using 17 cell lines and patient samples as positive controls. This testing included comparison with local protocols and primers as well as sensitivity testing via dilution experiments. The collaborative efforts resulted in standardized primer sets with a minimal target sensitivity of 10-2 for virtually all single PCR analyses, whereas the nested PCR analyses generally reached the minimal target sensitivity of 10-4. The standardized RT-PCR protocol and primer sets can now be used for molecular classification of acute leukemia at diagnosis and for MRD detection during follow-up to evaluate treatment effectiveness.
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PMID:Standardized RT-PCR analysis of fusion gene transcripts from chromosome aberrations in acute leukemia for detection of minimal residual disease. Report of the BIOMED-1 Concerted Action: investigation of minimal residual disease in acute leukemia. 1060 11

Calpain is a calcium-dependent cysteine protease that is implicated in calcium-dependent cell death, and calpain inhibitors are generally considered as inhibitors of apoptosis. To the contrary, in the present study, we found that calpain inhibitor II (CPI-2) triggers rapid apoptosis in acute lymphoblastic leukemia (ALL) and non-Hodgkin's lymphoma (NHL) cells. All target cell lines were killed by CPI-2, including: ALL-1, a multidrug-resistant BCR-ABL fusion transcript-positive t(9;22) pro-B ALL cell line; RS4;11, a highly radiation-resistant MLL-AF4 fusion transcript-positive t(4;11) pre-pre B ALL cell line; RAMOS, a highly radiation-resistant and p53-deficient Burkitt's lymphoma cell line; DAUDI, a Burkitt's leukemia/lymphoma cell line; NALM-6, a pre-B ALL cell line; and JURKAT and MOLT-3, two T-lineage ALL/NHL cell lines. CPI-2-induced apoptosis in LYN-deficient and BTK-deficient subclones of the DT-40 lymphoma B cell line as effectively as it did in wild-type DT-40 cells. Thus, CPI-2-induced apoptosis is not dependent on the protein tyrosine kinases LYN or BTK. Notably, caspase inhibitor I effectively inhibited CPI-2-induced apoptosis, suggesting that the inhibition of a CPI-2-susceptible protease results in caspase activation, leading to apoptosis in ALL/NHL cells. Unlike the high calpain-expressing ALL/NHL cell lines, myeloid leukemia cell lines HL-60/AML, K562/CML, and U937/AMML, or solid tumor cell lines BT-20/breast cancer, PC-3/prostate cancer, U373/glioblastoma, and HeLa/epitheloid cancer, were not susceptible to the cytotoxicity of CPI-2. Taken together, our results identify calpain as a new molecular target for the treatment of ALL and NHL. CPI-2 and its analogues represent a promising new class of antileukemia/lymphoma agents that deserves further development.
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PMID:Calpain inhibitor II induces caspase-dependent apoptosis in human acute lymphoblastic leukemia and non-Hodgkin's lymphoma cells as well as some solid tumor cells. 1087 99

B-cell precursor acute lymphoblastic leukemias (BCP-ALLs) are increasingly treated on risk-adapted protocols based on presenting clinical and biological features. Residual molecular positivity of clonal immunoglobulin (IG) and T-cell receptor (TCR) rearrangements allows detection of patients at an increased risk of relapse. If these rearrangements are to be used for universal follow-up, it is important to determine the extent to which they are informative in different BCP-ALL subsets. We show that IGH V-D-J rearrangements occur in 89% of 163 BCP-ALL, with no significant variation according to age or genotype (BCR-ABL, TEL-AML1, MLL-AF4, and E2A-PBX1). In contrast, TCRG rearrangements, which occur in 60% of patients overall, are frequent in BCR-ABL and TEL-AML1, are less so in MLL-AF4, and are virtually absent in infants aged predominantly from 1 to 2 years and in E2A-PBX1 ALLs. Incidence of the predominant TCRD Vdelta2-Ddelta3 rearrangement decreases with age but is independent of genotype. These differences are not due to differential recombination activating gene activity, nor can they be explained adequately by stage of maturation arrest. Analysis of MLL-AF4 BCP-ALL is in keeping with transformation of a precursor at an early stage of ontogenic development, despite the adult onset of the cases analyzed. We postulate that the complete absence of TCRG rearrangement in E2A-PBX1 cases may result from deregulated E2A function. These data also have practical consequences for the use of TCR clonality for the molecular follow-up of BCP-ALL.
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PMID:The incidence of clonal T-cell receptor rearrangements in B-cell precursor acute lymphoblastic leukemia varies with age and genotype. 1097 74


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