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)

Neurotrophins (NTs) and their receptors play a key role in neurogenesis and survival. The TRK (tropomyosin-related kinase) receptor protein tyrosine kinases (TRKA, TRKB, TRKC) are high-affinity NT receptors that are expressed in a variety of human tissues. Their role in normal and malignant hematopoiesis is poorly understood. In a prospective study involving 94 adult patients we demonstrate for the first time cell-surface expression of the 3 TRKs and constitutive activation in blasts from patients with de novo or secondary acute leukemia. At least one TRK was expressed in 55% of the analyzed cases. We establish a clear correlation between the TRK expression pattern and FAB classification. Although only few point mutations were found in TRK sequences by reverse-transcriptase-polymerase chain reaction (RT-PCR), we observed coexpression of BDNF (ligand for TRKB) in more than 50% of TRKB(+) cases (16/30). Activation of TRKA or TRKB by NGF and BDNF, respectively, efficiently rescued murine myeloid cells from irradiation-induced apoptosis. Coexpression of TRKB/BDNF or TRKA/NGF in murine hematopoietic cells induced leukemia. Moreover, activation of TRKs was important for survival of both human and murine leukemic cells. Our findings suggest that TRKs play an important role in leukemogenesis and may serve as a new drug target.
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PMID:High-affinity neurotrophin receptors and ligands promote leukemogenesis. 1905 81

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

MLL is involved in chromosomal rearrangements that generate fusion proteins with deregulated transcriptional activity. The mechanisms of MLL fusion protein-mediated transcriptional activation are poorly understood. Here we show MLL interacts directly with the polymerase associated factor complex (PAFc) through sequences flanking the CxxC domain. PAFc interacts with RNA polymerase II and stimulates posttranslational histone modifications. PAFc augments MLL and MLL-AF9 mediated transcriptional activation of Hoxa9. Conversely, knockdown of PAFc disrupts MLL fusion protein-mediated transcriptional activation and MLL recruitment to target loci. PAFc gene expression is downregulated during hematopoiesis and likely serves to regulate MLL function. Deletions of MLL that abolish interactions with PAFc also eliminate MLL-AF9 mediated immortalization indicating an essential function for this interaction in leukemogenesis.
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PMID:The PAF complex synergizes with MLL fusion proteins at HOX loci to promote leukemogenesis. 2067 49

Recent studies aimed at elucidating the mechanism controlling HIV-1 transcription have led to the identification and characterization of two multi-subunit complexes that both contain P-TEFb, a human transcription elongation factor and co-factor for activation of HIV-1 gene expression by the viral Tat protein. The first complex, termed the 7SK snRNP, acts as a reservoir where active P-TEFb can be withdrawn by Tat to stimulate HIV-1 transcription. The second complex, termed the super elongation complex (SEC), represents the form of P-TEFb delivered by Tat to the paused RNA polymerase II at the viral long terminal repeat during Tat transactivation. Besides P-TEFb, SEC also contains other elongation factors/co-activators, and they cooperatively stimulate HIV-1 transcription. Recent data also indicate SEC as a target for the mixed lineage leukemia (MLL) protein to promote the expression of MLL target genes and leukemogenesis. Given their roles in HIV-1/AIDS and cancer, further characterization of 7SK snRNP and SEC will help develop strategies to suppress aberrant transcriptional elongation caused by uncontrolled P-TEFb activation. As both complexes are also important for normal cellular gene expression, studying their structures and functions will elucidate the mechanisms that control metazoan transcriptional elongation in general.
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PMID:New insights into the control of HIV-1 transcription: when Tat meets the 7SK snRNP and super elongation complex (SEC). 2136 54

The Super Elongation Complex (SEC), containing transcription elongation activators/coactivators P-TEFb, ELL2, AFF4/1, ENL, and AF9, is recruited by HIV-1 Tat and mixed lineage leukemia (MLL) proteins to activate the expression of HIV-1 and MLL-target genes, respectively. In the absence of Tat and MLL, however, it is unclear how SEC is targeted to RNA polymerase (Pol) II to stimulate elongation in general. Furthermore, although ENL and AF9 can bind the H3K79 methyltransferase Dot1L, it is unclear whether these bindings are required for SEC-mediated transcription. Here, we show that the homologous ENL and AF9 exist in separate SECs with similar but nonidentical functions. ENL/AF9 contacts the scaffolding protein AFF4 that uses separate domains to recruit different subunits into SEC. ENL/AF9 also exists outside SEC when bound to Dot1L, which is found to inhibit SEC function. The YEATS domain of ENL/AF9 targets SEC to Pol II on chromatin through contacting the human Polymerase-Associated Factor complex (PAFc) complex. This finding explains the YEATS domain's dispensability for leukemogenesis when ENL/AF9 is translocated to MLL, whose interactions with PAFc and DNA likely substitute for the PAFc/chromatin-targeting function of the YEATS domain.
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PMID:Human Polymerase-Associated Factor complex (PAFc) connects the Super Elongation Complex (SEC) to RNA polymerase II on chromatin. 2187 27

Long non-coding RNAs (lncRNAs) are functional RNAs longer than 200 nucleotides in length. LncRNAs are as diverse as mRNAs and they normally share the same biosynthetic machinery based on RNA polymerase II, splicing and polyadenylation. However, lncRNAs have low coding potential. Compared to mRNAs, lncRNAs are preferentially nuclear, more tissue specific and expressed at lower levels. Most of the lncRNAs described to date modulate the expression of specific genes by guiding chromatin remodelling factors; inducing chromosomal loopings; affecting transcription, splicing, translation or mRNA stability; or serving as scaffolds for the organization of cellular structures. They can function in cis, cotranscriptionally, or in trans, acting as decoys, scaffolds or guides. These functions seem essential to allow cell differentiation and growth. In fact, many lncRNAs have been shown to exert oncogenic or tumor suppressor properties in several cancers including haematological malignancies. In this review, we summarize what is known about lncRNAs, the mechanisms for their regulation in cancer and their role in leukemogenesis, lymphomagenesis and hematopoiesis. Furthermore, we discuss the potential of lncRNAs in diagnosis, prognosis and therapy in cancer, with special attention to haematological malignancies.
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PMID:Long non-coding RNAs in haematological malignancies. 2388 58

RNA leukemia viruses induce T-cell lymphoblastic lymphomas or myeloid leukemias. Infection of cells with Moloney murine leukemia virus (M-MuLV) up-regulates the expression of a number of cellular genes, including those involved in T-lymphocyte activation. Previously, we demonstrated that this up-regulation occurs via the trans-activation activity of the M-MuLV long terminal repeat (LTR) sequences which produce an LTR-encoded transcript. Sequence analysis of the LTR revealed a potential transcription unit for RNA polymerase III (Pol III) within the U3 region that is actively occupied by Pol II factors. Here, we provide the direct evidence of involvement of Pol III in the trans-activation process and demonstrate the precise localization of the intragenic control elements for accurate and active Pol III transcription. Deletions of a copy of the directed repeats and further immediate upstream sequences significantly abrogated the generation of LTR-encoded transcript and abolished the trans-activational activity, whereas the deletion of a copy of directed repeats alone proportionally reduced the transcript size, but still retained moderately high trans-activational activity. In electrophoretic mobility shift assay, the fraction containing a multiple transcription factor TFIIIC complex strongly bound to the LTR-U3 probe containing the essential control elements. The specificity of the DNA-TFIIIC interaction was confirmed by conducting competition assays with DNA fragments containing a genuine Pol III-transcribed gene, VA1, and by vaccinia virus infection which stimulates the expression of Pol III factors. However, a deletion mutant lacking an essential control element bound to the TFIIIC complex poorly, consequently resulting in weak Pol III transcription as assessed by an IRES-GFP reporter system. This correlation strongly supports the possibility that the generation of LTR-encoded transcript is directed by Pol III. Therefore, this finding suggests the involvement of Pol III transcription in the retrovirus-induced activation of cellular genes, potentially contributing to leukemogenesis.
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PMID:RNA polymerase III control elements are required for trans-activation by the murine retroviral long terminal repeat sequences. 2544 7

The t(16;21)(p11;q22) is a rare chromosomal abnormality that appears in approximately 1% of acute myeloid leukemia (AML) cases. Previously, between 50 and 60 cases have been reported. In this review, we will discuss the literature regarding t(16;21) as well as cases published. We compiled 68 cases from the Mitelman Database of Chromosome Aberrations and Gene Fusions in Cancer as well as 10 additional cases in the literature, for a total of 78 cases. The t(16;21) results in the TLS(FUS)-ERG fusion protein, which is believed to function as a transcriptional activator in leukemogenesis and has been demonstrated to interfere in normal pre-mRNA splicing functions of FUS/TLS. Reverse-transcriptase polymerase chain reaction of fusion transcripts in patients, has been demonstrated to have diagnostic significance in monitoring for minimal residual disease. Cytogenetically, about half of the cases had secondary chromosomal abnormalities; we found that trisomy 8 and 10 were the most common abnormalities, occurring in 9.1% of the otal cases for each. t(16;21) in AML has been described with various morphological features, such as phagocytosis and vacuolation, and is present in multiple FAB types. Immunophenotypic characteristics such as CD33 and CD34 expression have also been noted, and several studies have examined the relation between CD56 receptor expression and t(16;21) AML. In general, t(16;21) in AML is associated with a poor prognosis and this abnormality could serve as cytogenetic indicator in determining diagnosis and prognosis. Herein, we summarize the cytogenetic features found in the the Mitelman Database of Chromosome Aberrations and Gene Fusions in Cancer for t(16;21) in AML, as well as review the current literature associated with t(16;21), AML and its features.
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PMID:A t(16;21)(p11;q22) in Acute Myeloid Leukemia (AML) Resulting in Fusion of the FUS/TLS and ERG Genes: A Review of the Literature. 2718 48

STAG2 encodes a cohesin component and is frequently mutated in myeloid neoplasms, showing highly significant comutation patterns with other drivers, including RUNX1. However, the molecular basis of cohesin-mutated leukemogenesis remains poorly understood. Here we show a critical role of an interplay between STAG2 and RUNX1 in the regulation of enhancer-promoter looping and transcription in hematopoiesis. Combined loss of STAG2 and RUNX1, which colocalize at enhancer-rich, CTCF-deficient sites, synergistically attenuates enhancer-promoter loops, particularly at sites enriched for RNA polymerase II and Mediator, and deregulates gene expression, leading to myeloid-skewed expansion of hematopoietic stem/progenitor cells (HSPC) and myelodysplastic syndromes (MDS) in mice. Attenuated enhancer-promoter loops in STAG2/RUNX1-deficient cells are associated with downregulation of genes with high basal transcriptional pausing, which are important for regulation of HSPCs. Downregulation of high-pausing genes is also confirmed in STAG2-cohesin-mutated primary leukemia samples. Our results highlight a unique STAG2-RUNX1 interplay in gene regulation and provide insights into cohesin-mutated leukemogenesis. SIGNIFICANCE: We demonstrate a critical role of an interplay between STAG2 and a master transcription factor of hematopoiesis, RUNX1, in MDS development, and further reveal their contribution to regulation of high-order chromatin structures, particularly enhancer-promoter looping, and the link between transcriptional pausing and selective gene dysregulation caused by cohesin deficiency.This article is highlighted in the In This Issue feature, p. 747.
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PMID:Combined Cohesin-RUNX1 Deficiency Synergistically Perturbs Chromatin Looping and Causes Myelodysplastic Syndromes. 3224 13


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