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)

The SCID mouse represents a valuable tool for assessing growth characteristics and drug sensitivity of human leukemic cells. We have examined differences in the engraftment patterns in SCID mice of primary human leukemic cells isolated from children (< 21 years old) with either t(1;19)+/E2A-PBX1+ or t(9;22)+/BCR-ABL+ acute lymphoblastic leukemia. Leukemic cells from 13/24 t(1;19)+/E2A-PBX1+ patients caused overt leukemia in SCID mice. Macroscopic lesions were evident in 6/13 cases, with multiple sites involved in some mice: hepatomegaly,(3) splenomegaly(4), thymic enlargement; liver tumors(1), kidney tumors(1), abdominal tumors(1). Microscopic lesions in SCID mouse organs were present in all 13 cases and involved the bone marrow, brain, heart, gut, liver, kidney, lung, ovary, pancreas, skeletal muscle, spleen, and thymus. Leukemic cells from 5/20 t(9;22)+/BCR-ABL+ patients caused overt leukemia in SCID mice. Notably, macroscopic lesions (splenomegaly; leukemic bones; hepatic tumors) were observed in only 1 case. In all 5 cases, microscopic lesions were found in the mouse bone marrow. Additional microscopic lesions were restricted to skeletal muscle, spleen, and mesentery (1 case) or thymus (1 case). These findings differ markedly from those of t(1;19)+/E2A-PBX1+ leukemic cells due to the lack of involvement of major organs such as liver, pancreas, kidney, skin, or brain. These data illustrate the biological heterogeneity of childhood ALL and suggest that the differential risks associated with t(1;19)+/E2A-PBX1+ and t(9;22)+/BCR-ABL ALL might arise from unique engraftment and proliferation capabilities of the respective leukemic cell populations.
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PMID:Distinct in vivo engraftment and growth patterns of t(1;19)+/E2A-PBX1+ and t(9;22)+/BCR-ABL+ human leukemia cells in SCID mice. 1003 3

The pattern of expression of the human Emt tyrosine kinase was established in healthy individuals and hematological malignancies by RT-PCR from bone marrow and blood samples, fractionated into T-cells, B-cells, monocytes, granulocytes and thrombocytes. Previously studied mostly in murine samples or established human cell lines, the in vivo correlation was here further clarified. In hematopoietic cells, expression of the EMT gene was associated with T-cell fractions, but Emt was not detected in cord blood CD34+ cells. In fetal tissues, Emt mRNA was strongly expressed in thymus, no expression could be detected in non-hematopoietic tissues. The expression pattern of the 48 malignant bone marrow samples (23 ALL, 1 PLL, 9 AML, 7 CLL and 8 CML cases) paralleled the findings from normal hematopoietic cells: 9/11 T cell associated ALLs, as well as one T-PLL sample, but only 1/12 samples of B-ALL expressed Emt markedly. Only minor signs of Emt expression could be shown in the AML samples, while CML and CLL samples were totally devoid of expression. In addition the Emt protein could be detected by Western blotting from T-lymphocytes and T-cell associated ALL, corresponding to mRNA expression. In conclusion, Emt (Itk) is T-cell associated both in normal and leukemic cells, but is not expressed in cord blood CD34+ cells, suggesting that Emt expression is switched on only later in T-cell development. In addition, an association between Emt and CD2 expression remains even in malignancies.
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PMID:Human Emt tyrosine kinase is specifically expressed both in mature T-lymphocytes and T-cell associated hematopoietic malignancies. 1004 24

Translocation t(9;22) or Philadelphia chromosome (Ph)/BCR-ABL rearrangement positive acute lymphoblastic leukemia (Ph/BCR+ ALL) is associated with a very short survival of about one year in most patients. We analyzed long-term outcome of 76 adults with Ph/BCR+ ALL, in order to detect which factors were associated with longer survival. Modifiable prognostic factors included type of treatment, allogeneic marrow transplant (allo-BMT), and early anthracycline dose intensity (high = H/A, low = L/A); unmodifiable factors were age, gender, FAB morphology, phenotype, blast count, P190/210 transcript, hepatospleno-lymphadenopathy, LDH level. Median patient age was 43 years (range 15-71). Four favorable prognostic factors (FPF) were found associated with greater likelihood of complete remission (blast count < 50 x 10(9)/l, p = 0.08), longer remission duration (age < 50 years, p < 0.001; H/A, p < 0.05), and lower relapse rate (allo-BMT, p = 0.017). Age and anthracycline dose intensity exerted a synergistic prognostic effect. According to the cumulative incidence of FPF in each patient (FPF 0-1 = 29, 2-3 = 42, 4 = 5), the probability of survival increased from nil to 0.22 to 0.60 at 5 years (p < 0.005). Adult Ph/BCR+ ALL is relatively sensitive to anthracyclines, which therefore should be prescribed at full dosage to patients not eligible to allo-BMT or in the waiting list for unrelated donor transplantation.
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PMID:Clinical sensitivity to anthracyclines in PH/BCR+ acute lymphoblastic leukemia. 1050 Aug 26

BCR-ABL is a chimeric oncogene generated by translocation of sequences from the chromosomal counterpart (c-ABL gene) on chromosome 9 into the BCR gene on chromosome 22. Alternative chimeric proteins, BCR-ABL(p190) and BCR-ABL(p210), are produced that are characteristic of chronic myelogenous leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph(1)-ALL). In CML, the transformation occurs at the level of pluripotent stem cells. However, Ph(1)-ALL is thought to affect progenitor cells with lymphoid differentiation. Here we demonstrate that the cell capable of initiating human Ph(1)-ALL in non-obese diabetic mice with severe combined immunodeficiency disease (NOD/SCID), termed SCID leukemia-initiating cell (SL-IC), possesses the differentiative and proliferative capacities and the potential for self-renewal expected of a leukemic stem cell. The SL-ICs from all Ph(1)-ALL analyzed, regardless of the heterogeneity in maturation characteristics of the leukemic blasts, were exclusively CD34(+ )CD38(-), which is similar to the cell-surface phenotype of normal SCID-repopulating cells. This indicates that normal primitive cells, rather than committed progenitor cells, are the target for leukemic transformation in Ph(1)-ALL.
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PMID:A primitive hematopoietic cell is the target for the leukemic transformation in human philadelphia-positive acute lymphoblastic leukemia. 1078 38

Single-step Multiplex RT-PCR was used as a rapid and highly sensitive method for screening patients with myeloproliferative conditions and ALL for the presence of underlying BCR-ABL gene fusions. Positive and negative results obtained with the multiplex assay were subsequently confirmed by nested PCR. We studied 21 patients for detecting the presence of b3a2, b2a2 and e1a2 BCR-ABL transcripts at diagnosis and following treatment with different therapeutical procedures. These studies allowed the molecular characterisation of patients with different haematological disorders and for demonstrating BCR-ABL transcripts in Ph-CML. In a Ph+ CML patient, a switch of isoforms was detected after bone marrow transplantation and infusion with donor lymphocytes, implying substitution of e1a2 for b3a2 coexisting with a myeloid/lymphoid biphenotypic profile. In ALL, one Ph+ patient showed coexpression of e1a2 and b2a2 at diagnosis followed by persistence of e1a2 after bone marrow transplantation. Our results were compared to previous findings in the literature on molecular diagnosis of leukaemias.
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PMID:Detection of BCR-ABL transcripts by multiplex and nested PCR in different haematological disorders. 1072 88

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

A unique variant Philadelphia translocation accompanied by the loss of the short arm of chromosome 9 in a 32-year-old female with common acute lymphoblastic leukemia (cALL) is described. Furthermore, supernumerary chromosome 8 material was found as an insertion into the long arm of chromosome 2 and/or as ring chromosomes in addition to two normal chromosomes 8. The chromosomal abnormalities were identified by combined conventional chromosome banding analysis and fluorescence in situ hybridization (FISH). The BCR-ABL rearrangement was confirmed by FISH and reverse transcriptase-polymerase chain reaction (RT-PCR) studies. Possible mechanisms leading to this variant intra Philadelphia translocation are discussed. The aberrations found have prognostic implications, because 9p anomalies confer an adverse effect to the already poor prognosis of Philadelphia-positive ALL.
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PMID:Variant intra philadelphia translocation with rearrangement of BCR-ABL and ABL-BCR within the same chromosome in a patient with cALL. 1110 16

Molecular genetic and cytoimmunological markers have been applied for the detection of minimal residual disease (MRD) in hematological malignancies. These markers include surface markers or rearranged T-cell receptor and immunoglobulin genes in the lymphoid malignancies and fused genes associated with chromosomal translocations such as BCR-ABL in t(9;22) or PML-RAR alpha in t(15;17) in myeloid malignancies. The expression of the WT1 gene is recognized as the universal tumor marker for a wide variety of hematological malignancies. Using these sensitive markers, a tumor cell in 10,000 to 1,000,000 normal cells can be detected. By examining a large number of patients, it has been shown that the MRD in the early phase of chemotherapy has a correlation with the prognosis of childhood ALL. Based on these observations, a new strategy of chemotherapy in which the post-remission therapy is modified based on the MRD results has begun. The amount of tumor cells contaminated in the autologous stem cell grafts in ALL patients might be related to the prognosis. The diagnosis of MRD will be used as an important routine examination in chemotherapy for leukemia/lymphoma patients.
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PMID:[The minimal residual disease (MRD) in hematological malignancies]. 1143 42

STI571, a BCA-ABL tyrosine kinase inhibitor, has appeared in molecular targeted therapy as a new treatment option for patients with chronic myelogenous leukemia (CML) through rational drug development. In a phase I study in the USA, adverse effects were minimal. Complete hematologic response was observed in 98% of patients with chronic phase CML treated with a daily dose of 300 mg or more, and cytogenetic response was seen in 31% of patients. STI571 has substantial activity in the blast crisis of CML and Ph + ALL. Stem cell transplantation (SCT) may be compared with interferon-alpha (IFN-alpha) therapy from three analyses reported according to risk assessment. These studies indicated that SCT increased survival only in patients who were younger and at intermediate or high risk; however, survival with SCT in older patients at higher risk was no better than with IFN-alpha therapy in a Japanese prospective study. An individualized risk assessment-based approach is useful in prioritizing SCT and IFN-alpha in patients with chronic phase CML.
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PMID:[Chronic myelogenous leukemia]. 1157 30

The Ph chromosome has been genetically linked to CML and ALL. Its chimeric fusion gene product, BCR-ABL, can generate leukemia in mice. This review will discuss selected model systems developed to study BCR-ABL induced leukemia and focuses on what we have learned about the human disease from these models. Five main experimental approaches will be discussed including: (i) Reconstitution of mice with bone marrow cells retrovirally transduced with BCR-ABL; (ii) Transgenic mice expressing BCR-ABL; (iii) Knock-in mice with BCR-ABL expression driven from the endogenous bcr locus; (iv) Development of CML-like disease in mice with loss of function mutations in heterologous genes; and (v) ES in vitro hematopoietic differentiation coupled with regulated BCR-ABL expression.
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PMID:Modeling Philadelphia chromosome positive leukemias. 1160 16


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