Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.10.2 (focal adhesion kinase)
 44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The translocation (6;9) in acute nonlymphocytic leukemia results in the formation of a dek-can fusion gene. In a case of acute undifferentiated leukemia, the oncogene can is fused to a different gene, named set, instead of dek and is assumed to be activated. Transcripts of set encode a putative SET protein with a predicted molecular mass of 32 kDa. We identified SET as a 39-kDa protein by immunoprecipitation with rabbit antiserum against each of three synthetic peptides predicted from the open reading frame of the set gene. We confirmed this identification of SET by protein sequencing. We also observed that SET is expressed ubiquitously in various human cell lines. SET is phosphorylated on serine residue(s) in cultured cells and is localized predominantly in nuclei. Although the function(s) of SET and SET-CAN is not known, we propose that SET plays a key role in the mechanism of leukemogenesis in acute undifferentiated leukemia, perhaps by activating CAN in nuclei and stimulating the transformation potential of SET-CAN. This proposed role would therefore be similar to the roles observed for BCR and DEK of the chimeric oncoproteins BCR-ABL and DEK-CAN in acute myeloid leukemia and acute nonlymphocytic leukemia, respectively.
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PMID:Identification and characterization of SET, a nuclear phosphoprotein encoded by the translocation break point in acute undifferentiated leukemia. 829 83

The Philadelphia (Ph) translocation [t(9;22)(q34;q11)] is the most common genetic abnormality in human leukemia; a transposition of the ABL gene to the major-breakpoint cluster region (M-BCR) is associated with the pathogenesis in Ph+ chronic myelogenous leukemia (Ph+ CML) and in some cases of Ph+ acute leukemia (Ph+ AL). Our current understanding of the methylation of human genomes allows us to consider the association between the epigenetic phenomenon and the control of differentiation and proliferation in mammalian cells. In order to determine whether the methylation status of the M-BCR is associated with breakpoint-localization in this region and with the lineage of hematopoietic cells, we have examined 28 patients with Ph+ leukemias, including nine with Ph+ AL, six patients with acute myeloblastic leukemia without Ph (Ph- AML), and five patients with Ph- acute lymphoblastic leukemia (Ph- ALL); using the restriction endonuclease isochizomers, MspI and HpaII. In CML patients in the chronic phase, the hypomethylated status within the normal M-BCR allele is heterogeneous. In contrast, patients with Ph+ CML in the lymphoid blast crisis phase exhibited a 2.5/2.7 kb band with a complete disappearance of the germline M-BCR fragment (type L). This pattern is consistently noted in Ph- ALL cells, and the pattern is quite different from that found in myeloid blast crisis or Ph- AML (type M). In patients with M-BCR-nonrearranged Ph+ ALL, it is suggested that the M-BCR methylation patterns are cell-lineage specific but some Ph+ ALL cells had a hypomethylation pattern that was identical to that observed in Ph- AML, suggesting a distinction of genetic diversity of leukemia cells with the Ph chromosome, especially Ph+ AL.
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PMID:The methylation status of the major breakpoint cluster region in human leukemia cells, including Philadelphia chromosome-positive cells, is linked to the lineage of hematopoietic cells. 850 75

TEL is a member of the Ets family of transcription factors which are frequently rearranged in human leukemia. The mechanism of TEL-mediated transformation, however, is unknown. We report the cloning and characterization of a chromosomal translocation associated with acute myeloid leukemia which fuses TEL to the ABL tyrosine kinase. The TEL-ABL fusion confers growth factor-independent growth to the marine hematopoietic cell line Ba/F3 and transforms Rat-1 fibroblasts and primary murine bone marrow cells. TEL-ABL is constitutively tyrosine phosphorylated and localizes to the cytoskeleton. A TEL-ABL mutant containing an ABL kinase-inactivating mutation is not constitutively phosphorylated and is nontransforming but retains cytoskeletal localization. However, constitutive phosphorylation, cytoskeletal localization, and transformation are all dependent upon a highly conserved region of TEL termed the helix-loop-helix (HLH) domain. TEL-ABL formed HLH-dependent homo-oligomers in vitro, a process critical for tyrosine kinase activation. These experiments suggest that oligomerization of TEL-ABL mediated by the TEL HLH domain is required for tyrosine kinase activation, cytoskeletal localization, and transformation. These data also suggest that oligomerization of Ets proteins through the highly conserved HLH domain may represent a previously unrecognized phenomenon.
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PMID:Oligomerization of the ABL tyrosine kinase by the Ets protein TEL in human leukemia. 875 9

Blastic transformation of chronic myelogenous leukemia (CML) is characterized by the presence of nonrandom, secondary genetic abnormalities in the majority of Philadelphia1 clones, and loss of p53 tumor suppressor gene function is a consistent finding in 25-30% of CML blast crisis patients. To test whether the functional loss of p53 plays a direct role in the transition of chronic phase to blast crisis, bone marrow cells from p53+/+ or p53-/- mice were infected with a retrovirus carrying either the wild-type BCR/ABL or the inactive kinase-deficient mutant, and were assessed for colony-forming ability. Infection of p53-/- marrow cells with wild-type BCR/ABL, but not with the kinase-deficient mutant, enhanced formation of hematopoietic colonies and induced growth factor independence at high frequency, as compared with p53+/+ marrow cells. These effects were suppressed when p53-/- marrow cells were coinfected with BCR/ ABL and wild-type p53. p53-deficient BCR/ABL-infected marrow cells had a proliferative advantage, as reflected by an increase in the fraction of S+G2 phase cells and a decrease in the number of apoptotic cells. Immunophenotyping and morphological analysis revealed that BCR/ABL-positive p53-/- cells were much less differentiated than their BCR/ABL-positive p53+/+ counterparts. Injection of immunodeficient mice with BCR/ABL-positive p53-/- cells produced a transplantable, highly aggressive, poorly differentiated acute myelogenous leukemia. In marked contrast, the disease process in mice injected with BCR/ABL-positive p53+/+ marrow cells was characterized by cell infiltrates with a more differentiated phenotype and was significantly retarded, as indicated by a much longer survival of leukemic mice. Together, these findings directly demonstrate that loss of p53 function plays an important role in blast transformation in CML.
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PMID:Blastic transformation of p53-deficient bone marrow cells by p210bcr/abl tyrosine kinase. 891 57

Seven secondary leukemia patients were treated for solid tumors or malignant lymphoma with anticancer drugs or radiation. We studied bone marrow samples from these patients by fluorescence in situ hybridization (FISH). Of the seven patients, three had increased signals for the ABL oncogene (9q34) on interphase nuclei and at metaphase. One of the three patients also had four signals for the CD3 (MLL) region (11q23). Whole painting probes revealed that these chromosomal regions were translocated onto structurally abnormal chromosomes, resulting in partial tri-, tetra- or penta-somy of these regions. We called this type of translocation "segmental jumping translocation (SJT)." SJT of the ABL oncogene was not detected in samples from 15 patients with de novo acute myelocytic leukemia (AML), 12 with myelodysplastic syndrome (MDS), or 20 with chronic myelocytic leukemia (CML) at the chronic phase. Furthermore, monosomy 7 was also found in the patients with the gene amplification. These results indicate that SJT of ABL and/or CD3 (MLL) genes is associated with the leukemogenesis of secondary leukemia. The SJT may be one mechanism of gene amplification.
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PMID:Frequent jumping translocations of chromosomal segments involving the ABL oncogene alone or in combination with CD3-MLL genes in secondary leukemias. 900 63

This report describes a precise molecular analysis of a rare case of Philadelphia chromosome (Ph) positive acute myeloid leukemia (AML) (FAB classification M2). Phenotypic markers were positive for cells of the myeloid lineage, but negative for B cell and T cell lineage. The leukemic cells carried a Philadelphia chromosome. Major breakpoint cluster region (M-BCR) rearrangement was detected by the Southern blot analysis. Reverse transcriptase polymerase chain reaction analysis revealed the presence of b3a2 BCR/ABL mRNA transcripts. The patient achieved complete remission by conventional remission induction therapy for acute myeloid leukemia. M-BCR rearrangement could not be detected during complete remission. After hematological remission of an 8-month duration, the patient relapsed and died of respiratory distress due to pneumonia. Our case indicate Ph-positive AML with M-BCR rearrangement actually exists. Ph-positive AML carries either M-BCR rearrangement expressing the P210 BCR-ABL or minor breakpoint cluster region (m-BCR) rearrangement producing the P190 BCR-ABL. Therefore, additional other factor (s) apart from the Ph chromosome must be responsible for the acute malignant transformation.
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PMID:Molecular analysis of a case of Philadelphia chromosome-positive acute myeloid leukemia. 906 90

We performed fluorescence in situ hybridization (FISH) upon 9;22 and 15;17 translocation-positive bone marrow cells to monitor the clinical course of 46 patients with chronic myelocytic leukemia (CML) and nine with acute promyelocytic leukemia (AML M3) who received chemotherapy and/or bone marrow transplantation (BMT). M-BCR-ABL and PML-RAR alpha probes were used to detect translocations of t(9;22) and t(15;17), respectively. Signals from CML patients treated with interferon (17 patients) or BMT (29 patients) were 0.5-15% positive for the 9;22 translocation. Among nine M3 patients who received extensive chemotherapy or BMT, 1-5% were positive for the 15;17 translocation. A highly sensitive FISH procedure using both translocation probes and a whole chromosome Y probe was established and applied to eight sex-mismatched BMT patients (seven CML and one AML M3), in which 0.1-0.6% of signals positive for the specific translocations were detected. These results suggested that interphase FISH is powerful enough to identify minor cell populations of 9;22 or 15;17 translocations after therapy, as well as to detect specific chromosome abnormalities at diagnosis.
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PMID:Application of fluorescence in situ hybridization to detect residual leukemic cells with 9;22 and 15;17 translocations. 906 86

Fluorescence in situ hybridization (FISH) and the reverse transcription-polymerase chain reaction (RT-PCR) were used to examine a patient presenting with acute myelogenous leukemia (AML) FAB M2, and a complex t(4;9;22)(p14;q34;q11.2). The patient's clinical course was characterized by an aggressive leukemia, resistant to intensive therapy including allogeneic bone marrow transplantation. FISH analysis, using two chromosome painting probes and a BCR/ABL specific probe, confirmed the cytogenetic observation of a 22q11.2-->4p14 and a 4p14-->9q34 exchange, and revealed the presence of a 9q34-->22q11.2, respectively. In addition, RT-PCR demonstrated the presence of a BCR/ABL transcript derived from the major breakpoint cluster region (M-bcr) of the BCR gene. This transcript has been shown to generate an active 210 kDa tyrosine kinase protein more commonly observed in chronic myelogenous leukemia. Because the presentation of AML with this ABL-->BCR fusion product is a rare event, it would seem likely that the additional complex chromosomal rearrangement involving chromosomes 4, 9, and 22 played a role in the aggressive presentation and clinical behavior of this patient's leukemia.
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PMID:Complex chromosome 4, 9, and 22 rearrangement in a patient presenting with AML-FAB M2. 907 96

We assessed the chimerism of CD34+ bone marrow cells before donor leukocyte infusion (DLI) on nine occasions in seven patients with leukemic relapse after allogeneic marrow transplantation. The patients suffered from acute lymphoblastic leukemia (n = 1), acute myeloid leukemia (n = 3), and chronic myeloid leukemia (CML; n = 3). Two patients received a second DLI because of disease progression after the first one. The origin of the CD34+ cells was determined by analyzing variable number of tandem repeats with polymerase chain reaction and, in sex-mismatched cases, by fluorescence in situ hybridization. Before DLI CD34+ cells were exclusively of donor origin in four patients. In another patient 41% of CD34+ cells were derived from the donor. No aplasia occurred in these patients after DLI, whereas in the two patients with exclusively recipient hematopoiesis severe aplasia lasting for 5 and 13 weeks necessitated hematopoietic stem cell support. One patient who had only 5% CD34+ donor cells before DLI recovered without stem cell support after 10 days. Two patients in relapse of CML showed a high percentage of BCR-ABL- CD34+ cells of recipient origin before DLI. These BCR-ABL- cells of recipient type did not prevent severe aplasia which indicates that the assessment of BCR-ABL+ hematopoiesis alone is insufficient for predicting aplasia. Our data indicate that in case of sufficient donor hematopoiesis before DLI no persistent aplasia will occur. Thus, evaluation of donor hematopoiesis allows prediction of aplasia after DLI and makes early therapeutic interventions possible.
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PMID:Donor leukocyte infusion for leukemic relapse after allogeneic marrow transplantation: lack of residual donor hematopoiesis predicts aplasia. 912 13

We report a case of Philadelphia (Ph)-positive AML in which interphase fluorescence in situ hybridization (FISH) analysis was performed from diagnosis throughout the course of therapy using major (M-) breakpoint cluster region (BCR)/minor (m-) BCR and ABL cosmid probes. We also investigated the existence of the M-BCR or m-BCR at the RNA or DNA level by the reverse transcriptase polymerase chain reaction and Southern blot analysis, respectively. Complete remission with a normal karyotype was achieved after several regimens of chemotherapy and peripheral blood stem cell transplantation (PBSCT), but relapse occurred and his cells became 100% Ph-positive. We detected the m-BCR/ABL fusion gene by interphase FISH analysis using an m-BCR/ABL translocation probe, and found that FISH analysis was useful for classifying the BCR, identifying minimal residual disease, and for predicting imminent relapse after chemotherapy and PBSCT.
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PMID:Sequential interphase FISH analysis of m-BCR/ABL chimeric gene-positive cells in Ph-positive acute myeloid leukemia. 925 Aug 5


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