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

---

Query: EC:2.7.10.2 (focal adhesion kinase)
44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have previously reported the establishment of an interleukin-3 (IL-3)-dependent and phenotypically myeloid cell line (TALL-103/3), obtained by culturing cells from an immature T-lymphoblastic leukemia in the presence of IL-3. These cells differentiated into a T-lymphoid cell line (TALL-103/2) upon removal of IL-3 and incubation in IL-2. Despite the different phenotype, the two cell lines remained karyotypically and genotypically identical. Here, we have analyzed the phenotypic changes and the signaling events induced by these two lymphokines in TALL-103/3 cells by switching them to temporary growth in IL-2 and returning them to IL-3. All four sublines obtained (the myeloid in IL-3 and the lymphoid in IL-2) expressed RNA for CD3, IL-2 receptor (R) alpha, and T-cell receptor (TCR)-gamma and -delta chains. However, cells cultured in IL-3 failed to express detectable levels of the IL-2R beta chain at both the protein and RNA levels, whereas cells exposed to IL-2 always expressed IL-2R beta. In parallel with the changes in IL-2R beta expression, the SRC-like protein tyrosine kinase (PTK) p56 LCK could not be detected in IL-3-dependent cells, but was abundant in the IL-2-dependent cells and underwent markedly increased autophosphorylation in response to IL-2. In contrast, p53/p56 LYN was highly expressed in IL-3-dependent cells, and greatly decreased when these cells were switched to growth in IL-2. LYN kinase autophosphorylation modestly increased in response to IL-3. None of the other kinases in the SRC family that were tested underwent increased autophosphorylation after lymphokine stimulation, indicating the specificity of IL-2 for LCK and of IL-3 for LYN. The TALL-103 cell lines provide a unique system to study the interaction between lymphokines and SRC-family PTKs in signal transduction pathways leading to hematopoietic cell differentiation.
...
PMID:Phenotypic changes induced by interleukin-2 (IL-2) and IL-3 in an immature T-lymphocytic leukemia are associated with regulated expression of IL-2 receptor beta chain and of protein tyrosine kinases LCK and LYN. 137 47

A case of T lymphoblastic leukemia (T-ALL) showing t(1;7)(p34;q34) as the sole karyotypic abnormality was investigated at the molecular level. Screening of a phage library of tumor DNA with a probe for the beta T cell receptor gene (TCRB), which maps to chromosomal band 7q34, resulted in the isolation of a clone containing DNA spanning the translocation breakpoint of the der(1) chromosome. This clone contained chromosome 1 DNA juxtaposed upstream of a D beta-J beta joint. Cloning of the corresponding germline region of chromosome 1 resulted in the isolation of a phage containing the breakpoint from the reciprocal, der(7), product, which showed chromosome 1 DNA joined downstream to a V beta segment. Comparison of germline and translocation clones demonstrated that breakage of chromosome 1 had occurred at the border of a tandem repeat of Alu sequences. To search for transcripts from DNA near the breakpoint, a chromosomal walk was initiated along chromosome 1. A probe consisting of chromosome 1 DNA from 24-30 kb upstream of the breakpoint hybridized to a transcript derived from the gene encoding the lymphocyte-specific tyrosine kinase p56lck, previously mapped to chromosomal band 1p34. The nonrandom nature of the breakpoints in this case was confirmed by the analysis of a second independent case of T-ALL containing a t(1;7) translocation, which was also found to show breakage within the LCK locus. The chromosomal breakpoint in the first case was localized 2 kb upstream of the lck upstream promoter and first nontranslated exon, while the breakpoint of the second case lay between the two alternative lck promoters, upstream of the second exon. Relative to normal thymus and activated T cells, levels of lck mRNA were greatly elevated in the first case and moderately elevated in the second. The existence of these translocations raises the possibility that alterations in the promoter region of the LCK locus may play a role in human cancer.
...
PMID:Chromosomal translocations joining LCK and TCRB loci in human T cell leukemia. 168 Sep 58

A patient is described with de novo acute non-lymphocytic leukemia of megakaryoblastic lineage with tri-lineage myelodysplasia. This patient was studied cytogenetically and using molecular genetic techniques throughout her clinical course. She had an N-ras mutation at diagnosis which persisted despite a bone marrow transplant, and acquired a Philadelphia chromosome associated with a P190 BCR-ABL transcript at clinical relapse 3 months post-transplantation.
...
PMID:Megakaryoblastic leukemia with an N-ras mutation and late acquisition of a Philadelphia chromosome. 188 21

Expression of the 93-kd tyrosine kinase encoded by the human c-fes proto-oncogene (also known as FES) is restricted to mature hematopoietic cells of the granulocytic and monocytic lineages, suggestive of a function essential to normal myeloid differentiation. However, recent studies have shown that c-fes can transform fibroblasts if sufficient levels of gene expression are achieved. These findings indicate that strict regulation of the c-fes gene is critical to normal myeloid development, whereas elevated c-fes expression may contribute to malignant transformation. In the present study, we compared the c-fes messenger RNA (mRNA) levels in leukemia blasts from patients with myeloid or lymphoid leukemia with those of peripheral monocytes from a normal donor with the use of a quantitative ribonuclease protection assay. The presence of c-fes mRNA was readily detected in both acute myeloid leukemia (AML) and chronic myeloid leukemia (CML) cells, but c-fes mRNA was present in low levels or was absent in lymphoid leukemia cells. The leukemia cells of two of five AML patients and four of four CML patients expressed more c-fes mRNA than monocytes from a normal donor, with more than a threefold elevation in the cells of one CML patient. No evidence of amplification or rearrangement of the c-fes gene was detectable by Southern blot analysis of myeloid leukemia DNA, suggesting that the variation in c-fes mRNA levels are related to differences in transcriptional activity and/or message stability. These results indicate that elevated c-fes expression is a common feature of myeloid leukemia cells that could potentially contribute to the leukemia phenotype.
...
PMID:Elevated expression of the c-fes proto-oncogene in adult human myeloid leukemia cells in the absence of gene amplification. 198 16

A translocation between chromosomes 7 and 9, t(7;9), has been described in cell lines derived from the malignant cells of children with acute T-cell lymphoblastic leukemia or lymphoma. Our cytogenetic analysis of one such cell line, SUP-T3, demonstrates that the breakpoints on chromosomes 7 and 9 lie within bands q36 and q34, respectively, corresponding to the location of the gene encoding the beta chain of the T-cell receptor, TCRB, and the gene homologous to the transforming gene of the Abelson murine leukemia virus, ABL. We investigated the role of these genes in the t(7;9). In situ chromosomal hybridization of TCRB and ABL probes to metaphase cells from SUP-T3 demonstrated that ABL is translocated from chromosome 9 to 7 and that all or part of TCRB is translocated from chromosome 7 to 9. Southern blot analysis revealed that both TCRB alleles were rearranged; however, it could not be determined whether the translocation breakpoint lies within this gene. Pulsed-field gel electrophoresis and Southern blot analysis were used to examine more than 500 kilobases of the ABL locus; we concluded that there are no rearrangements within 250 kb in either direction of the sequences homologous to v-abl. Additionally, no abnormal ABL protein was detected in an in vitro phosphorylation assay. These results indicate that, in SUP-T3, the breakpoint on chromosome 9 lies proximal to ABL and that the break results in no apparent alteration of the ABL protein. We therefore hypothesize that another gene on chromosome 9, at band q34, plays a role in this translocation. This study also demonstrates that pulsed-field gel electrophoresis is a powerful new tool for the analysis of human chromosomal translocations.
...
PMID:Molecular analysis of TCRB and ABL in a t(7;9)-containing cell line (SUP-T3) from a human T-cell leukemia. 302 59

The human BCR-ABL oncogenes encoded by the Philadelphia chromosome (Ph) affect the pathogenesis of diverse types of leukemia and yet are rarely associated with T-lymphoid leukemia. To determine whether BCR-ABL kinases are inefficient in transforming T lymphocytes, BCR-ABL-expressing retroviruses were injected intrathymically into mice. Thymomas that expressed BCR-ABL kinase developed after a relatively long latent period. In most thymomas, deletion of 3' proviral sequences resulted in loss of tk-neo and occasionally caused expression of kinase-active carboxy-terminally truncated BCR-ABL oncoprotein. In contrast, deletion of 3' proviral sequences was not observed in thymomas induced with Abelson murine leukemia virus (A-MuLV). BCR-ABL viruses induced distinct patterns of disease and involved different thymocyte subsets than A-MuLV and Moloney murine leukemia virus (Mo-MuLV). While Mo-MuLV only induced Thy-1+ thymomas, v-abl- and BCR-ABL-induced thymomas often contained mixed populations of B220+ and Thy-1+ lymphocytes in the same tumor. In most v-abl and BCR-ABL tumors, Thy-1+ lymphoid cells expressed CD8 and a continuum of CD4 ranging from negative to positive. Conversely, Mo-MuLV thymomas contained distinct populations of CD4+ cells that were either CD8+ or CD8-. A-MuLV-transformed T-lymphoid cells did not express the CD3/T-cell receptor complex, while BCR-ABL tumors were CD3+. Thus, BCR-ABL viruses preferentially induce somewhat more differentiated T lymphocytes than are transformed by A-MuLV. Furthermore, rare B220+ lymphocytes may represent preferred v-abl and BCR-ABL transformation targets in the thymus.
...
PMID:BCR-ABL and v-abl oncogenes induce distinct patterns of thymic lymphoma involving different lymphocyte subsets. 839 67

Chronic myelogenous leukemia (CML) can sometimes present in lymphoid blast phase (L-BP), and can be difficult to distinguish from Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL). Some have suggested that the determination of cell lineages involved by the Ph chromosome may be used for distinguishing CML presenting in L-BP (presumably multilineage disease) from Ph+ ALL (presumably lymphoid-restricted), although others have suggested the term 'stem cell ALL' for the multilineage process. Because it has been difficult to perform lineage studies of the Ph chromosome, we investigated the use of fluorescence in situ hybridization (FISH) with probes for BCR (on chromosome 22) and ABL (on chromosome 9) to study lineage involvement in Ph+ lymphoblastic malignancies. We analyzed routine blood and marrow specimens from eight patients who presented with Ph+ lymphoblastic leukemia and found that FISH recognized the 9;22 translocation, distinguished between the two common molecular variants, and readily identified multilineage vs lymphoblast-restricted disease. In our series, four patients had multilineage and four had lymphoblast-restricted disease. Multilineage disease was associated with morphologic features of CML at diagnosis and/or reversion to chronic phase CML after treatment leading us to consider it as CML presenting in L-BP. Patients with lymphoid-restricted disease lacked such findings. The survival of three of our four patients with multilineage disease was prolonged, at 25, 28+, and 126+ months, and when data from our entire series are added to those of 18 previously reported cases that were studied for lineage involvement (reviewed in Leukemia 1993; 7: 147), the difference in overall survival between patients with multilineage and lymphoblast-restricted disease is significant (median overall survival of 47 months vs 8 months, respectively; P=0.013, log rank). Our findings illustrate that FISH analysis can be used to recognize lineage involvement in patients presenting with Ph+ lymphoblastic malignancies, and they provide further support to the notion that multilineage and lymphoblast-restricted disease are distinct clinically as well as biologically.
...
PMID:Lineage involvement by BCR/ABL in Ph+ lymphoblastic leukemias: chronic myelogenous leukemia presenting in lymphoid blast vs Ph+ acute lymphoblastic leukemia. 865 74

Interleukin-11(rhIL-11) is a cytokine that has been shown to enhance the recovery of bone marrow and intestinal crypt cells after cytotoxic insult with radiation or anticancer drugs. The current study examined the effects of rhIL-11 on the response of CEM human lymphoblastic leukemia cells and on the EMT-6 murine mammary carcinoma in vivo to cytotoxic anticancer therapies. Exposure of CEM cells to rhIL-11 for 24 hr did not alter the cytotoxicity of melphalan or radiation, increased the cytotoxicity of CDDP (100 muM) and 4-hydroperoxycyclophosphamide (50 betaM) and decreased the cytotoxicity of 5-fluorouracil and ara-C toward the cells. Treatment of mice bearing the EMT-6 tumor with rhIL-11 twice daily for 4 days prior to and the day of cytotoxic therapy resulted in no significant change in the tumor cell killing or bone marrow CFU-GM killing by melphalan, cyclophosphamide, thiotepa, CDDP, radiation, 5-fluorouracil or ara-C. Administration of rhIL-11 twice per day on days 7-18 to EMT-6 tumor bearing animals receiving high dose chemotherapy (melphalan, thiotepa or cyclophosphamide) as a single dose on day 7 followed by mobilized peripheral blood cells on day 8 and rhG-CSF on days 8-20, tended to prolong the tumor growth delay produced by the drugs. This rhIL-11 treatment also resulted in a more rapid recovery of white blood cells and granulocytes in the animals. Furthermore, animals treated with rhIL-11 had improved survival rates compared with animals receiving all other normal tissue support without rhIL-11.
...
PMID:Interaction of interleukin-11 with cytotoxic therapies in vitro against CEM cells and in vivo against EMT-6 murine mammary carcinoma. 882 60

Translocations in hematologic disease of myeloid or lymphoid origin with breakpoints at chromosome band 12p13 frequently result in rearrangements of the Ets variant gene 6 (ETV6). As a consequence either the ETS DNA-binding domain or the Helix-Loop-Helix (HLH) oligomerization domain of ETV6 is fused to different partner genes. We show here that a t(9;12)(p24;p13) in a case of early pre-B acute lymphoid leukemia and a t(9;15;12)(p24;q15;p13) in atypical chronic myelogenous leukemia in transformation involve the ETV6 gene at 12p13 and the JAK2 gene at 9p24. In each case different fusion mRNAs were found, with only one resulting in an open reading frame for a chimeric protein consisting of the HLH oligomerization domain of ETV6 and the protein tyrosine kinase (PTK) domain of JAK2. The cloning of the complete human JAK2 coding and genomic sequences and of the genomic junction fragments of the translocations allowed a characterization of the different splice events leading to the various mRNAs. JAK2 plays a central role in non-protein tyrosine kinase receptor signaling pathways, which could explain its involvement in malignancies of different hematologic lineages. Besides hop in Drosophila no member of the JAK family has yet been implicated in tumorigenesis.
...
PMID:Fusion of TEL, the ETS-variant gene 6 (ETV6), to the receptor-associated kinase JAK2 as a result of t(9;12) in a lymphoid and t(9;15;12) in a myeloid leukemia. 932 18

BCR/ABL fluorescent in situ hybridization study of chronic myeloid leukemia (CML) and Philadelphia(+) (Ph(+)) acute lymphoid leukemia (ALL) indicated that approximately 9% of patients exhibited an atypical hybridization pattern consistent with a submicroscopic deletion of the 5' region of ABL and the 3' region of the BCR genes on the 9q(+) chromosome. The CML patients with deletions had a shorter survival time and a high relapse rate following bone marrow transplant. Since deletions are associated with both Ph(+) CML and ALL, it seemed probable that other leukemia-associated genomic rearrangements may also have submicroscopic deletions. This hypothesis was confirmed by the detection of deletions of the 3' regions of the CBFB and the MLL genes in AML M4 patients with inv(16) and in patients with ALL and AML associated with MLL gene translocations, respectively. In contrast, analysis of the AML M3 group of patients and AML M2 showed that similar large deletions were not frequently associated with the t(15;17) or t(8;21) translocations. Analysis of sequence data from each of the breakpoint regions suggested that large submicroscopic deletions occur in regions with a high overall density of Alu sequence repeats. These findings are the first to show that the process of deletion formation is not disease specific in leukemia and also implicate that the presence of repetitive DNA in the vicinity of breakpoint regions may facilitate the generation of submicroscopic deletions. Such deletions could lead to the loss of one or more genes, and the associated haploinsufficiency may result in the observed differences in clinical behavior. (Blood. 2001;97:3581-3588)
...
PMID:Primary chromosomal rearrangements of leukemia are frequently accompanied by extensive submicroscopic deletions and may lead to altered prognosis. 1136 54


1 2 3 4 5 6 7 8 Next >>

---