Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.30.2 (endonuclease)
 18,621 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Fludarabine phosphate selectively eliminates normal and malignant mononuclear cells in large animals and man through the inhibition of DNA synthesis. The drug depletes mononuclear cells from culture within 24 hours of initial exposure, CD4 and CD8 T cells being more sensitive than either CD20 B cells or CD34 bone marrow precursors. Mitogenic activation of lymphocytes enhances cellular elimination from culture. Fludarabine inhibits PHA-induced T-cell proliferation by >90 per cent and mixed lymphocyte reactions (allogeneic and xenogeneic) by >95 per cent. Fludarabine exerts its cytolytic effects through the induction of endonuclease-independent apoptosis. A 5-day course of fludarabine (50 mg/m2 intravenously once daily) induces both T- and B-cell lymphopenia in Cynomolgus monkeys and Papio baboons. Transient neutropenia was the only side-effect seen in experimental animals. Pretreatment of Cynomolgus monkeys with this regimen of fludarabine causes a prolongation of ABO-compatible skin allograft survival from 8 days (control) to 16 days (drug treated group). Secondary allotransplantation into presensitized recipients showed a similar prolongation of graft survival with fludarabine pretreatment (8 days vs 5 days control). Fludarabine promises to be a potent immunosuppressive agent with low clinical toxicity.
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PMID:Fludarabine phosphate: A DNA synthesis inhibitor with potent immunosuppressive activity and minimal clinical toxicity. 865 23

The most common gene fusion (up to 25%) in childhood acute lymphoblastic leukemia (ALL) is that between ETV6 and RUNX1 (previously TEL and AML1, respectively; we here use the old nomenclature, for ease of reference to the literature). We determined the incidence of TEL/AML1 translocation with reverse transcriptase polymerase chain reaction (RT-PCR) and flow-cytometric immunophenotyping of newly diagnosed pediatric acute lymphoblastic leukemia patients in Thailand. The TEL/AML1 fusion genes were cloned into plasmids and sequenced. The variant found was confirmed with restriction fragment length polymorphism (RFLP) using SphI restriction endonuclease. Of 35 ALL patients, we found an incidence of 8.6% of TEL/AML1 translocation in ALL patients (12% of B-lineage ALL), which is lower than that reported in caucasians but is similar to that reported in Japanese and Koreans. All the translocation-positive patients had B-lineage common ALL, expressing CD10+. Interestingly, the two TEL/AML1 subclones were CD20 negative, and one subclone expressed a myelocytic marker (CD33+). Two TEL/AML1 subclones from bone marrow of ALL patients were isolated and sequenced. One was a wild type and the other was a variant having A --> G substitution at nucleotide 73 from the 5' end. The substitution nucleotide was located in the AML1 region. The clinical relevance of the variant is to be investigated.
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PMID:Cloning and sequencing of ETV6/RUNX1 (TEL/AML1) variant in acute lymphoblastic leukemia. 1510 90

Many B-lineage-specific genes are down-regulated in Hodgkin and Reed-Sternberg (HRS) cells of classical Hodgkin lymphoma (cHL). We investigated the involvement of epigenetic modifications in gene silencing in cHL cell lines and in microdissected primary HRS cells. We assessed the expression and methylation status of CD19, CD20, CD79B, SYK, PU.1, BOB.1/OBF.1, BCMA, and LCK, all of which are typically down-regulated in cHL. We could reactivate gene expression in cHL cell lines with the DNA demethylating agent 5-aza-deoxycytidine (5-aza-dC). Using methylation-specific polymerase chain reaction (MSP), bisulfite genomic sequencing, and digestion with methylation-sensitive endonuclease followed by polymerase chain reaction (PCR), we determined the methylation status of promoter regions of PU.1, BOB.1/OBF.1, CD19, SYK, and CD79B. Down-regulation of transcription typically correlated with hypermethylation. Using bisulfite genomic sequencing we found that in microdissected HRS cells of primary cHL SYK, BOB.1/OBF.1, and CD79B promoters were also hypermethylated. Ectopic expression of both Oct2 and PU.1 in a cHL cell line potentiated endogenous PU.1 and SYK expression after 5-aza-dC treatment. These observations indicate that silencing of the B-cell-specific genes in cHL may be the consequence of a compromised regulatory network where down-regulation of a few master transcription factors results in silencing of numerous genes.
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PMID:Epigenetic processes play a major role in B-cell-specific gene silencing in classical Hodgkin lymphoma. 1630 50