Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.7.49 (reverse transcriptase)
 31,746 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Acute promyelocytic leukemia (APL) is typified by the reciprocal translocation, t(15; 17)(q22; q21), leading to the formation of PML-RARalpha and RARalpha-PML fusion genes. We have characterized 7 cases of morphologic APL found to lack the t(15; 17) on conventional cytogenetic assessment. In 6 of 7 cases, cryptic PML-RARalpha rearrangements were identified by reverse transcriptase-polymerase chain reaction and fluorescent in situ hybridization (FISH); whereas, in the remaining patient, APL was associated with the variant translocation, t(11; 17)(q23; q12-21), leading to the formation of PLZF-RARalpha and RARalpha-PLZF fusion genes. In each of the cases with cryptic PML-RARalpha rearrangements, PML-RARalpha transcripts were detected in the absence of RARalpha-PML, consistent with the concept that PML-RARalpha is the critical oncogenic fusion protein. In 4 of these cases with evaluable metaphase spreads, the occurrence of a nonreciprocal translocation was confirmed by FISH with sole formation of the PML-RARalpha fusion gene; in 3 cases with morphologically normal chromosomes 15 and 17, RARalpha was inserted into PML on 15q, whereas in the remaining patient the PML-RARalpha fusion arose due to insertion of 15q-derived material including PML into RARalpha on 17q. Immunofluorescence studies were performed using antibodies raised against PML and PIC 1, a ubiquitin-homology domain protein previously identified as an interaction partner of PML. In acute myeloid leukemia (AML) of subtypes other than M3, PIC 1 was localized to the nuclear membrane and colocalized with PML within discrete nuclear bodies. In APL cases with cryptic PML-RARalpha rearrangements, the characteristic microparticulate pattern of PML staining was detected with partial colocalization with PIC 1, indicative of disruption of the nuclear bodies; whereas in t(11; 17)-associated APL, PML and PIC 1 remained colocalized within discrete nuclear bodies, as observed in non-APL cases. Although deregulation of the putative growth suppressor PML and delocalization of other nuclear body constituents have been advocated to play a key role in the development of t(15; 17)-associated APL, the present study shows that disruption of PML nuclear bodies per se is not a prerequisite for the pathogenesis of APL.
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PMID:Characterization of cryptic rearrangements and variant translocations in acute promyelocytic leukemia. 938 4

There are presently 42 million people worldwide living with HIV/AIDS, the majority of which have limited access to antiretrovirals. Even if worldwide penetration was possible, our current chemotherapeutic strategies still suffer from issues of cost, patient compliance, deleterious acute and chronic side effects, emerging single and multidrug resistance, and generalized treatment and economic issues. Even our best antiretroviral therapeutic strategy, highly active antiretroviral therapy (HAART), falls short of completely suppressing HIV replication. Therefore, expansion of current therapeutic options by discovering new antiretrovirals and targets will be critical in the coming years. This review addresses the current status of reverse transcriptase and protease inhibitor development, and summarizes the progress in emerging classes of HIV inhibitors, including entry (T-20, T-1249), coreceptor (SCH-C, SCH-D), integrase (beta-Diketos) and p7 nucleocapsid Zn finger inhibitors (thioesters and PATEs). In addition, the processes of virus entry, PIC transport to the nucleus, HIV interaction with nuclear pores, Tat function, Rev function and virus budding (Tsg101 and ubiquitination) are examined, and proof of concept inhibitors and potential antiviral targets discussed.
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PMID:The next generation of HIV/AIDS drugs: novel and developmental antiHIV drugs and targets. 1548 5

Macrophages are natural target cells of human immunodeficiency virus type 1 (HIV-1). Viral replication appears to be delayed in these cells compared to lymphocytes; however, little is known about the kinetics of early post-entry events. Time-of-addition experiments using several HIV-1 inhibitors and the detection of reverse transcriptase (RT) products with droplet digital PCR (ddPCR) revealed that early replication was delayed in primary human monocyte-derived macrophages of several donors and peaked late after infection. Direct imaging of reverse-transcription and pre-integration complexes (RTC/PIC) by click-labeling of newly synthesized DNA further confirmed our findings and showed a concomitant shift to the nuclear stage over time. Altering the entry pathway enhanced infectivity but did not affect kinetics of viral replication. The addition of viral protein X (Vpx) enhanced productive infection and accelerated completion of reverse transcription and nuclear entry. We propose that sterile alpha motif (SAM) and histidine/aspartate (HD) domain-containing protein 1 (SAMHD1) activity lowering deoxyribonucleotide triphosphate (dNTP) pools is the principal factor delaying early HIV-1 replication in macrophages.
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PMID:Detailed Characterization of Early HIV-1 Replication Dynamics in Primary Human Macrophages. 3042 2