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)

Acute promyelocytic leukemia (APL) is a subtype of acute myeloid leukemia. Submicroscopic insertion of RARalpha into PML, resulting in PML-RARalpha from derivative chromosome 15, has been rarely reported. Herein, we describe a functional PML-RARalpha transcript from the long arm of derivative chromosome 17 in a patient with microgranular APL. The conventional karyotype showed normal chromosomes 15 and 17. It is interesting that interphase and metaphase fluorescence in situ hybridizations demonstrated a fusion signal on the long arm of one chromosome 17 homolog, with both PML and RARalpha still present on chromosomes 15 and 17, respectively, although the signal on one chromosome 15 was weaker, indicating partial loss of the PML gene. Reverse transcriptase-polymerase chain reaction revealed a transcript corresponding to a break cluster region 3 (bcr3) short form PML-RARalpha. To the best of our knowledge, this is the first report of an APL with a bcr3/short form PML-RARalpha transcript generated from derivative chromosome 17 due to submicroscopic insertion of the PML gene into the RARalpha locus.
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PMID:A bcr3/short form PML-RARalpha transcript in an acute promyelocytic leukemia resulted from a derivative chromosome 17 due to submicroscopic insertion of the PML gene into the RARalpha locus. 1909 67

Chromosomal 11p15 abnormality of therapy-related myelodysplastic syndrome (t-MDS)-acute myeloid leukemia (AML) is rare. NUP98-NSD3 fusion transcripts have been detected previously in one patient with AML and one patient with t-MDS having t(8;11)(p11;p15). Here we present the case of a 60-year-old man with radiation-associated MDS (r-MDS) carrying chromosome abnormalities, including t(8;11)(p11;p15) and del(1)(p22p32). Fluorescence in situ hybridization analysis demonstrated that the NUP98 gene at 11p15 was split by the translocation. Southern blot analysis of bone marrow cells showed both rearrangements of NUP98 and NSD3 genes. Reverse transcriptase-polymerase chain reaction (RT-PCR) followed by sequence analysis revealed the presence of both NUP98-NSD3 and NSD3-NUP98 fusion transcripts. Expression analysis by RT-PCR showed that NSD3 as well as NSD1 and NSD2 was ubiquitously expressed in leukemic cell lines and Epstein-Barr virus transformed B lymphocyte cell lines derived from the normal adult lymphocytes examined. Two isoforms of NSD3, NSD3S and NSD3L (but not NSD3L2), were expressed in leukemic cell lines and were fused to NUP98 in our patient, suggesting that qualitative change of these two isoforms of NSD3 by fusion with NUP98 might be related to leukemogenesis, although the function of each isoform of the NSD3 gene remains unclear.
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PMID:NUP98-NSD3 fusion gene in radiation-associated myelodysplastic syndrome with t(8;11)(p11;p15) and expression pattern of NSD family genes. 1938 29

PURPOSE To determine the prognostic importance of the meningioma 1 (MN1) gene expression levels in the context of other predictive molecular markers, and to derive MN1 associated gene- and microRNA-expression profiles in cytogenetically normal acute myeloid leukemia (CN-AML). PATIENTS AND METHODS MN1 expression was measured in 119 untreated primary CN-AML adults younger than 60 years by real-time reverse-transcriptase polymerase chain reaction. Patients were also tested for FLT3, NPM1, CEBPA, and WT1 mutations, MLL partial tandem duplications, and BAALC and ERG expression. Gene- and microRNA-expression profiles were attained by performing genome-wide microarray assays. Patients were intensively treated on two first-line Cancer and Leukemia Group B clinical trials. Results Higher MN1 expression associated with NPM1 wild-type (P < .001), increased BAALC expression (P = .004), and less extramedullary involvement (P = .01). In multivariable analyses, higher MN1 expression associated with a lower complete remission rate (P = .005) after adjustment for WBC; shorter disease-free survival (P = .01) after adjustment for WT1 mutations, FLT3 internal tandem duplications (FLT3-ITD), and high ERG expression; and shorter survival (P = .04) after adjustment for WT1 and NPM1 mutations, FLT3-ITD, and WBC. Gene- and microRNA-expression profiles suggested that high MN1 expressers share features with high BAALC expressers and patients with wild-type NPM1. Higher MN1 expression also appears to be associated with genes and microRNAs that are active in aberrant macrophage/monocytoid function and differentiation. CONCLUSION MN1 expression independently predicts outcome in CN-AML patients. The MN1 gene- and microRNA-expression signatures suggest biologic features that could be exploited as therapeutic targets.
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PMID:Prognostic importance of MN1 transcript levels, and biologic insights from MN1-associated gene and microRNA expression signatures in cytogenetically normal acute myeloid leukemia: a cancer and leukemia group B study. 1945 32

This study was purposed to investigate lrp16 gene expression in leukemia cell lines and bone marrow cells of leukemia patients and explore the relationship between lrp16 gene expression and development of leukemia. Reverse transcriptase-polymerase chain reaction (RT-PCR) was employed to test the lrp16 mRNA expression in 4 leukemia cell lines, including K562 (CML), HL-60 (APL), MOLT4 (ALL) and U937 cell lines, as well as in bone marrow-derived cells from 115 patients with leukemia. The effect of lrp16 gene expression on genesis and progression of leukemia was analyzed according to clinicopathological features. The results indicated that positive expression of lrp16 mRNA was found in all 4 leukemia cell lines. For leukemia patients, the positive expression rate of lrp16 mRNA in all AML patients was 38% (16/42), in which the positive rates in AML patients with complete remission (CR) and AML patients without remission were 13% (4/30) and 100% (12/12) respectively. The positive expression rate of lrp16 mRNA in ALL patients was 38% (10/26), in which the positive rate in ALL patients with CR and ALL patients without remission were 16% (3/18) and 87% (7/8) respectively. The positive expression rate of lrp16 mRNA in CML patients was 36% (9/25), in which the positive rates in CML patients with CR and CML patients without remission were 20% (4/20) and 100% (5/5) respectively. The positive rate of lrp16 mRNA in CLL patients was 31% (7/22), in which the positive rate in CLL patients with CR and CLL patients without remission were 11% (2/17) and 100% (5/5) respectively. There was no difference of lrp16 gene expression between leukemia subtypes, but there was statistical significant difference in lrp16 gene expression between CR patients and non CR patients (p < 0.001). It is concluded that the lrp16 gene is a leukemic oncogene and closely relates to genesis and progression of leukemia, which may be an indicator for evaluating clinical efficacy of leukemia therapy.
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PMID:[Lrp16 gene expression in leukemia cell lines and bone marrow cells of leukemia patients and its clinical implication]. 1969 16

Triptolide, a natural product extracted from the Chinese plant Tripterygium wilfordii, possesses antitumor properties. Despite numerous reports showing the proapoptotic capacity and the inhibition of NF-kappaB-mediated transcription by triptolide, the identity of its cellular target is still unknown. To clarify its mechanism of action, we further investigated the effect of triptolide on RNA synthesis in the human non-small cell lung cancer cell line A549. Triptolide inhibited both total RNA and mRNA de novo synthesis, with the primary action being on the latter pool. We used 44K human pan-genomic DNA microarrays and identified the genes primarily affected by a short treatment with triptolide. Among the modulated genes, up to 98% are down-regulated, encompassing a large array of oncogenes including transcription factors and cell cycle regulators. We next observed that triptolide induced a rapid depletion of RPB1, the RNA polymerase II main subunit that is considered a hallmark of a transcription elongation blockage. However, we also show that triptolide does not directly interact with the RNA polymerase II complex nor does it damage DNA. We thus conclude that triptolide is an original pharmacologic inhibitor of RNA polymerase activity, affecting indirectly the transcription machinery, leading to a rapid depletion of short-lived mRNA, including transcription factors, cell cycle regulators such as CDC25A, and the oncogenes MYC and Src. Overall, the data shed light on the effect of triptolide on transcription, along with its novel potential applications in cancers, including acute myeloid leukemia, which is in part driven by the aforementioned oncogenic factors.
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PMID:Triptolide is an inhibitor of RNA polymerase I and II-dependent transcription leading predominantly to down-regulation of short-lived mRNA. 1980 79

We report two childhood cases of acute leukemia with t(16;21)(p11.2;q22) and FUS-ERG rearrangements. Patient 1 (14 years old) was initially diagnosed with acute myeloid leukemia. Chromosome study showed a t(16;21)(p11.2;q22) clone in more than one third of the cells analyzed, and further investigation with reverse-transcriptase polymerase chain reaction, cloning, and sequencing confirmed FUS-ERG rearrangement (type B). Patient 2 (8 months old) was diagnosed with acute lymphoblastic leukemia (ALL) on the basis of bone marrow morphology and immunophenotyping. Chromosome study revealed a 45,XY,-16,der(21)t(16;21)(p11.2;q22) in 50% of the cells analyzed. Further studies for the detection of a FUS-ERG chimeric transcript were conducted, and an unusual type of FUS-ERG rearrangement was discovered, which has been reported in only three patients including a 1-year-old infant with ALL. Although more clinical studies are necessary, we believe that a possible association between ALL and a specific type of FUS-ERG fusion transcript might be considered, especially in childhood cases with t(16;21).
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PMID:Two childhood cases of acute leukemia with t(16;21)(p11.2;q22): second case report of infantile acute lymphoblastic leukemia with unusual type of FUS-ERG chimeric transcript. 2062 Jun 4

We report a case of acute myeloid leukemia (AML) with two unrelated clones, one of which was t(11;17)(q23;q25) carrying MLL-SEPT9 fusion transcripts. The patient was a 71-year-old man who was diagnosed with AML M0 and received multiple chemotherapy regimens, including DNA topoisomerase II inhibitors. Although the karyotype of bone marrow cells at the initial diagnosis was normal, two unrelated chromosomal aberrations concurrently appeared during the course of the disease, suggestive of t(11;17)(q23;q25) and add(1)(p36.1),del(6)(q?) by G-banding. Spectral karyotyping analysis identified a reciprocal translocation between chromosomes 11 and 17, and a translocation of the q arm of chromosome 6 to chromosome 1. Dual-color fluorescence in situ hybridization analysis that used probes specific for MLL in combination with tel 1p and tel 1q revealed a translocation of 1p-->pter to chromosome 6 and a translocation of 11q23-->qter to chromosome 17. Reverse transcriptase-polymerase chain reaction and sequencing analyses demonstrated MLL-SEPT9 fusion transcripts with the breakpoint of MLL exon 8/SEPT9 exon 2 and MLL exon 9/SEPT9 exon 2. Thus, the karyotype was defined as 46,XY,t(11;17)(q23;q25)/46,XY,t(1;6)(p36.3;q23). Our case represents an additional MLL-SEPT9-positive AML that was considered to be related to therapy.
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PMID:Emergence of two unrelated clones in acute myeloid leukemia with MLL-SEPT9 fusion transcript. 2068 95

The ETS variant gene 6 (ETV6) gene is located at 12p13, and is frequently involved in translocations in various human neoplasms, resulting in the expression of fusion proteins consisting of the amino-terminal part of ETV6 and unrelated transcription factors or protein tyrosine kinases. Leukemia with t(1;12)(q21;p13) was previously described in a 5-year-old boy with acute myeloblastic leukemia (AML-M2) who exhibited a novel ETV6-aryl hydrocarbon receptor nuclear translocator (ARNT) fusion protein. We herein report the case of a 2-year-old boy with T-cell lymphoblastic leukemia (T-ALL) harboring t(1;12)(q21;p13). Fluorescence in situ hybridization (FISH) with a ETV6 dual-color DNA probe revealed that the split signals of the ETV6 gene in 96.7% of bone marrow cells, indicating rearrangement of the ETV6 gene. Therefore, we performed a FISH analysis with bacterial artificial chromosome (BAC) probes containing the ARNT, BCL9, and MLLT11 genes located at 1q21, and these results indicated that the ARNT gene might be involved in the t(1;12)(q21;p13). Reverse transcriptase-polymerase chain reaction analysis disclosed the existence of a ETV6-ARNT fusion gene. To our knowledge, the current report is novel in its report of the ETV6-ARNT fusion in childhood T-ALL. The ETV6-ARNT fusion is associated not only with AML but also with T-ALL.
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PMID:ETV6-ARNT fusion in a patient with childhood T lymphoblastic leukemia. 2080 16

The RUNX1 gene is frequently rearranged in de novo and therapy-related leukemia. In the present study, we identified the CLCA2 gene as a novel fusion partner of RUNX1 in a case of therapy-related acute myeloid leukemia associated with t(1;21)(p22;q22). Reverse transcriptase-polymerase chain reaction analysis and sequencing revealed that the t(1;21) results in out-of-frame RUNX1-CLCA2 fusions. Alternative splicing generates at least six fusion transcripts, including a major transcript fusing RUNX1 exon 6 with CLCA2 exon 2. These out-of-frame fusions produce putative truncated RUNX1 isoforms retaining the DNA binding Runt domain but not the transcriptional regulatory domain of RUNX1. No mutations were found in the exons encoding the Runt and C-terminal domains of the nonrearranged RUNX1 gene. Similar to truncated RUNX1 isoforms previously described, these shortened products could act as dominant negative inhibitors of RUNX1-dependent transactivation. CLCA2 is a breast tumor suppressor gene that encodes a member of the calcium-activated chloride channel family and is involved for the first time in a chromosomal translocation. The RUNX1-CLCA2 fusion is another example of out-of-frame fusion generating truncated RUNX1 isoforms that represent a recurrent molecular mechanism in RUNX1-related leukemias.
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PMID:CLCA2, a novel RUNX1 partner gene in a therapy-related leukemia with t(1;21)(p22;q22). 2087 71

A pericentric inv(9)(p22q34) of the derivative chromosome 9 that resulted from a standard t(9;22)(q34;q11.2) was identified by R-banding karyotypic analysis and fluorescence in situ hybridization (FISH) assays in 4 (0.18%) of 2,200 Philadelphia chromosome (Ph)-positive leukemia patients, including 3 with chronic myeloid leukemia (CML) in chronic phase and 1 with acute myeloid leukemia (AML) in our hospital since 2004. All four patients had two malignant clones: one with only t(9;22)(q34;q11.2) and another with der(9)t(9;22)(q34;q11.2)inv(9)(p22q34) that resulted in the separation of the ABL1/BCR fusion gene. No metaphases with only inv(9)(p22q34) were seen in any of them. FISH also found a deletion of partial sequence of BCR on der(9)t(9;22)(q34;q11.2)inv(9)(p22q34) in 67.5% of bone marrow cells in the AML patient, but did not detect the deletion of the sequence of ASS/9q34 in these four patients. Reverse transcriptase-polymerase chain reaction revealed a b3a2 type of BCR/ABL1 fusion transcript in all of them, proving their disease to be Ph-positive leukemia. On reviewing the literature, only two solitary Ph-positive leukemia patients have been noticed to have the inv(9)(p22q34) anomaly. These two patients, together with our four documented patients, indicate that inv(9)(p22q34) is a novel, rare, but recurrent secondary chromosomal abnormality for Ph-positive leukemia. Despite receiving hydroxyurea therapy (n = 3 patients), combined chemotherapy (n = 2), even imatinib treatment (n = 1), three patients, including one with AML and two with CML (one of whom progressed into the lymphoblastic blast phase), died with survival times of 28 days, 13 months, and 34 months, respectively. Only one patient with CML remained alive for 5.5 months. Their negative outcome implies that inv(9)(p22q34) has an unfavorable impact on prognosis. Presently, no firm conclusions can be drawn from this study. Because the case number reported here is very small, more patients with this anomaly need to be investigated to elucidate its true prognostic significance.
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PMID:A pericentric inv(9)(p22q34) of the der(9)t(9;22)(q34;q11.2) is a recurrent secondary anomaly in Ph-positive leukemia. 2115 55


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