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:2.7.7.6 (RNA polymerase)
34,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Here we report a rare chromosomal translocation, t(12;22)(p13;q11), which was detected in a 53-year-old female patient diagnosed as having minimally differentiated acute myeloid leukemia (AML-M0) according to the French-American-British classification criteria. Chromosome painting analysis with probes for chromosomes 12 and 22 confirmed the result of the conventional cytogenetic analysis. Reverse transcriptase polymerase chain reaction revealed the TEL-MN1 fusion transcript. Interestingly, she presented primary multidrug resistance and did not respond to several kinds of chemotherapy regimens. Moreover, she could not achieve remission after two doses of monotherapy with Mylotarg. Flow cytometry analysis detected high levels of expression of P-glycoprotein, multidrug-resistant-related protein, lung-related protein, and glutathione S-transferase pi in this case at presentation. As far as we know, this is the first report of t(12;22)(p13;q11) translocation involving TEL and MN1 genes in an AML-M0 patient.
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PMID:Minimally differentiated acute myeloid leukemia with t(12;22)(p13;q11) translocation showing primary multidrug resistance and expressing multiple multidrug-resistant proteins. 1747 96

EVI is a proto-oncogene that is activated in acute myeloid leukemia with chromosomal rearrangements that map to chromosome 3q26. We previously reported the clinicopathologic features of five cases of acute myeloid leukemia carrying t(3;8)(q26;q24). Using fluorescence in situ hybridization analysis, we demonstrate in the current study that the breakpoint on chromosome 3 is at EVI1/MDS1, and the breakpoint on chromosome 8 is just distal to the PVT1 oncogene homolog, a C-MYC activator in mice. The breakpoint on chromosome 8 was detected between the components of the LSI MYC dual-color break-apart rearrangement probe. Reverse-transcriptase polymerase chain reaction assay showed expression of EVI1 in all four cases analyzed, and DNA sequence analysis confirmed the findings. Reverse transcriptase polymerase chain reaction assay also demonstrated the expression of PVT1 and C-MYC in all four cases assessed. Western blot analysis detected EVI1 in one case analyzed. We conclude that the t(3;8)(q26;q24) results in deregulated EVI1 expression, similar to other balanced or unbalanced chromosomal translocations involving chromosome 3q26.
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PMID:Aberrant EVI1 expression in acute myeloid leukemias associated with the t(3;8)(q26;q24). 1769 89

A 5-year-old boy who initially presented with ALL and relapsed 4 months later with AML was found to have an add(19) in the leukemia cells. FISH revealed that the add(19) was really a cryptic t(l2;l9)(p13.3;p13.3) interrupting E2A (TCF3). Nucleotide sequences of cloned genomic fragments with the E2A rearrangements revealed that the der(12) contained E2A joined to an intron of the NOLI (p120) gene. Reverse transcriptase (RT)-PCR of patient lymphoblast RNA showed expression of in-frame fusion cDNAs consisting of most of NOL1 fused to the 3' portion of E2A that encoded part of the second transcriptional activation domain and the DNA binding and protein dimerization motifs. The reciprocal der(19) E2A genomic rearrangements included 5' regions of E2A joined to an intron of the ZNF384 (NMP4, CIZ) gene, located approximately 450 kb centromeric to NOL1 on chromosome 12. RT-PCR showed expression of in-frame E2A-ZNF384 fusion cDNAs. To our knowledge, this is the second report of a chromosome translocation in leukemia resulting in two different gene fusions. This is the first report of expression of E2A fusion protein that includes the DNA binding and protein dimerization domains due to a more proximal break in E2A compared to those described previously.
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PMID:E2A-ZNF384 and NOL1-E2A fusion created by a cryptic t(12;19)(p13.3; p13.3) in acute leukemia. 1818 22

Treatment of acute promyelocytic leukemia (APL) with a combination of anthracycline-based chemotherapy and all-trans retinoic acid (ATRA) leads to very high rates of complete remission and survival. There are only a limited number of publications on the development of therapy-related myelodysplastic syndrome (MDS) or acute myeloid leukemia during follow-up of APL. Although drugs targeting at DNA-topoisomerase II characteristically induce translocations involving 11q23, this was seldom seen in patients treated for APL. We report on a patient initially diagnosed with APL. Response to therapy was monitored by fluorescence in situ hybridization (FISH) and reverse-transcriptase polymerase chain reaction for the PML-RARalpha rearrangement. Consecutive samples showed a swift and complete reduction of PML-RARalpha rearranged cells. Twenty months after diagnosis, however, conventional cytogenetics revealed a complex karyotype with a translocation involving 11q23 and loss of chromosomes 7q and Xq. FISH analysis with the MLL probe identified 2q37 (harboring the SEPT2 gene) as the translocation partner of chromosome 11. We consider the rather unique t(2;11)(q37;q23) as the primary event causing therapy-related MDS in our patient. This case stresses the importance of conventional karyotyping to be performed on a regular basis in all treated APL patients for the early detection of chromosomal aberrations that indicate the development of therapy-related MDS or acute myeloid leukemia.
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PMID:Translocation (2;11)(q37;q23) in therapy-related myelodysplastic syndrome after treatment for acute promyelocytic leukemia. 1820 42

The aim of this study is to evaluate (1) the human telomerase-specific reverse transcriptase (hTERT) mRNA expression in childhood acute leukemia, (2) the association between the hTERT mRNA expression with the patients' characteristics and the known prognostic factors and (3) the correlation of the patients' survival with the initial hTERT mRNA value at diagnosis. A total of 40 newly diagnosed patients consist of children [31 cases with acute lymphoblastic leukemia (ALL) and 9 cases with acute myeloblastic leukemia (AML)] were prospectively included into the study. The online real-time reverse-transcriptase PCR was used for the quantification of hTERT in bone marrow (BM). All cases were re-evaluated for their survival after 2 years. The highest hTERT mRNA value was observed in Pre B-cell ALL patients followed by B-cell ALL, T-cell ALL and AML. The hTERT mRNA relative ratio difference between the ALL and AML groups was significant. No significant association was found when hTERT mRNA expression was evaluated in relation with the hematological parameters (except hemoglobin level), blast percentages and the risk groups. No significant difference was determined between the rate of complete remission and relapse of cases with the hTERT mRNA values in all malignancy groups. Patients who had higher initial hTERT mRNA values showed significantly longer disease-free survival (DFS) and overall survival (OS) in ALL (P = 0.000 and 0.01, respectively). Although DFS and OS was longer in AML patients with lower initial hTERT mRNA, the difference was not significant. In conclusion, the hTERT mRNA expression values were not significantly associated with the known prognostic factors in children both with ALL and AML. hTERT mRNA value is a significant factor for childhood ALL at diagnosis in relation to the estimated survival.
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PMID:The evaluation of hTERT mRNA expression in acute leukemia children and 2 years follow-up of 40 cases. 1829 58

Hexamethylene bis-acetamide-inducible protein 1 (HEXIM1) was identified earlier as an inhibitor of positive transcription elongation factor b (P-TEFb), which is a key transcriptional regulator of RNA polymerase II (Pol II). Studies show that more than half of P-TEFb in cells is associated with HEXIM1, which results in the inactivation of P-TEFb. Here, we identify a nucleolar protein, nucleophosmin (NPM), as a HEXIM1-binding protein. NPM binds to HEXIM1 in vitro and in vivo, and functions as a negative regulator of HEXIM1. Over-expression of NPM leads to proteasome-mediated degradation of HEXIM1, resulting in activation of P-TEFb-dependent transcription. In contrast, an increase in HEXIM1 protein levels and a decrease in transcription are detected when NPM is knocked down. We show that a cytoplasmic mutant of NPM, NPMc+, associates with and sequesters HEXIM1 in the cytoplasm resulting in higher RNA Pol II transcription. Correspondingly, cytoplasmic localization of endogenous HEXIM1 is detected in an acute myeloid leukemia (AML) cell line containing the NPMc+ mutation, suggesting the physiological importance of HEXIM1-NPMc+ interaction. Over-expression of NPM has been detected in tumors of various histological origins and our results may provide a possible molecular mechanism for the proto-oncogenic function of NPM. Furthermore, considering that 35% of AML patients are diagnosed with NPMc+ mutation, our findings suggest that in some cases of AML, RNA Pol II transcription may be disregulated by the malfunction of NPM and the mislocation of HEXIM1.
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PMID:Nucleophosmin interacts with HEXIM1 and regulates RNA polymerase II transcription. 1837 77

MLL located at 11q23 is fused with a variety of partner genes by recurrent chromosomal translocations in acute leukemias. ELL, the MLL partner gene located on chromosome 19p13.1, encodes an RNA polymerase II transcriptional elongation factor, which also possesses the N-terminal region involved in the inhibition of transcription initiation. Here we report a case of chronic myelomonocytic leukemia (CMML) with a 46,XY,t(11;19)(q23;p13.1) karyotype that transformed to acute myeloid leukemia (AML) without showing any karyotypic evolution. Interphase fluorescent in situ hybridization analysis showed the split MLL signals in 95% of bone marrow cells when the diagnosis of CMML was made and the percentage of blasts was 1.2%. Sequence analysis of reverse-transcriptional polymerase chain reaction product revealed a novel variant form of MLL-ELL transcript in which MLL exon 10 was fused to ELL exon 3. MLL has been fused to ELL exon 2 in all the previously reported MLL-ELL transcripts, which have always been associated with AML. It is deduced that the variant form of MLL-ELL may be defective not only in inhibition of transcription initiation, but also in transcriptional elongation. Thus, a possibility is raised that the unique clinical presentation of the present case with t(11;19)(q23;p13.1) might be related to the variant form of MLL-ELL.
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PMID:A novel variant form of MLL-ELL fusion transcript with t(11;19)(q23;p13.1) in chronic myelomonocytic leukemia transforming to acute myeloid leukemia. 1861 60

Acute myeloid leukemia (AML) represents a heterogeneous group of leukemia entities that differ with regard to biology, clinical course, and prognosis. Over the past decades, it has been shown that most AML cases exhibit chromosomal aberrations, gene mutations, and disordered gene expression that alter normal gene function, thereby contributing to leukemic transformation. Especially, in cytogenetically normal AML (CN-AML) molecular genetic and gene expression analyses are becoming of increasing importance. In addition to the impact of gene mutations, including the MLL, FLT3, CEBPA, or NPM1 genes in CN-AML, recent analyses have provided evidence that altered gene expression might not only be of biological but also of prognostic relevance in CN-AML patients. Quantitative reverse-transcriptase polymerase chain reaction (Q-RT-PCR) and recent advances in genome-wide DNA microarray-based gene expression profiling (GEP) represent powerful tools for the systematic exploration of the molecular variation underlying the biologic and clinical heterogeneity of CN-AML. Ultimately, a better understanding of gene expression alterations and hence the molecular basis of the disease will contribute to a refined leukemia classification, which will include both previously known CN-AML subgroups and novel classes defined by distinct gene expression clusters with prognostic significance.
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PMID:Gene expression with prognostic implications in cytogenetically normal acute myeloid leukemia. 1869 86

Nested reverse-transcriptase polymerase chain reaction (rt-PCR) was performed on 58 leukemia patients at BIRDEM Laboratory, as a pioneering work in Bangladesh. Thirty of themwere examined for the presence of BCR-ABL being clinically and morphologically diagnosed as chronic myeloid leukemia (CML) and 28 for PML-RARalpha fusion transcripts being clinically and morphologically diagnosed as acute promyelocytic leukemia (APL/ AML M3). The cases were selected for targeted therapy with imatinib mesylate and all-Trans retinoic acid (ATRA) to treat CML and APL respectively. Samples were received either before commencement or during therapy. In the positive cases, amplified DNA products were visible after gel electrophoresis and were reported accordingly. In case of BCR-ABL, positive results were found for five out of six (83.33%) untreated cases and 11 out of 24 (45.83%) treated cases. Positive results for PML-RARalpha were found for 12 out of 14 (85.70%) untreated cases and 11 out of 16 (68.75%) treated cases. A strong positive correlation was found between duration of treatment and negativity of PCR results in both the cases. In present times, the detection of minimal residual disease in patients undergoing treatment for hematological malignancies has become an important goal, not only to monitor the effectiveness of therapy but also to detect an impending relapse. This is the first time in Bangladesh that rt-PCR method is being employed to detect or monitor the presence of abnormal fusion genes in hematological malignancies.
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PMID:Rt-PCR method for diagnosis and follow-up of hematological malignancies: first approach in Bangladesh. 1878 70

Patients with infant acute myeloid leukemia (AML) who carry a t(7;12)(q36;p13) translocation have been reported to have a poor clinical outcome. MNX1-ETV6 fusion transcripts (previously HLXB9-ETV6) were rarely detected in AML patients having t(7;12)(q36;p13). A 23-month-old girl with acute megakaryoblastic leukemia (AMKL) exhibited chromosome abnormalities, including add(7)(q22), and del(12)(p12p13). Southern blot analysis of bone marrow cells showed an ETV6 gene rearrangement. Reverse transcriptase-polymerase chain reaction (RT-PCR) followed by sequence analysis revealed the presence of an MNX1-ETV6 fusion gene. The patient responded well to chemotherapy, achieved complete remission, and at writing had been in complete remission for 60 months. The MNX1 expression by RT-PCR was significantly more frequent in Epstein-Barr virus-transformed B-cell lines derived from normal adult lymphocytes than in leukemic cell lines. This represents a novel case of an AMKL patient with MNX1-ETV6 fusion transcripts who had a good prognosis.
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PMID:MNX1-ETV6 fusion gene in an acute megakaryoblastic leukemia and expression of the MNX1 gene in leukemia and normal B cell lines. 1894 Apr 75


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