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Targeting aberrant transcriptional repression in leukemia: a therapeutic reality?
| Content Provider | Semantic Scholar |
|---|---|
| Author | Licht, Jonathan D. |
| Copyright Year | 2001 |
| Abstract | The discovery that transcription factors are frequently disrupted in leukemia has led to efforts to target these proteins with drugs. These efforts have met with limited success, partly because it has proved difficult to design and deliver into the nucleus small molecules that might break up interactions between transcription factors and their target genes or cofactors. Hence the belief that transcription factors are not “druggable.” However, the pathogenic fusion proteins of leukemia have a common ability to aberrantly repress target genes, through recruitment of histone deacetylases (HDACs) and other enzymes that can be targeted by small organic molecules. Suberoylanilide hydroxamic acid (SAHA) is an HDAC inhibitor (HDI) entering clinical trials that may reverse aberrant repression by fusion proteins. Acute promyelocytic leukemia (APL) results from a chromosomal translocation in which the retinoic acid receptor gene (RARα) becomes fused to any of five partners (1). In the absence of ligand, corepressors like N-CoR bind to RAR, recruiting HDACs. Physiological levels of retinoic acid (RA) induce the release of corepressors and binding of coactivators with histone acetyl transferase activity. While deacetylated histone tails hinder transcription, lysine acetylation of the tails favors gene expression (2). In t(15;17) APL, the PML-RAR fusion protein has abnormally high affinity for corepressors and the protein switches to an activator only at pharmacological doses of RA (3). Such treatment provides one example of successful transcription-based therapy. t(11;17) yields the PLZF-RAR fusion protein and an RA-resistant form of the disease (1). PLZF is a transcriptional repressor (4) and complexes with corepressors and HDACs (5). Unlike PML-RAR, the PLZF-RAR fusion protein fails to release corepressors under the influence of RA, explaining the ineffectiveness of this treatment. However, HDIs such as trichostatin A and butyrate (3) block repression of reporter genes by PLZF-RAR. Whether reversal of transcriptional repression explains the efficacy of the drug combination in vivo is unclear. In the current issue of the JCI, He et al. (6) show that only the combination of RA and SAHA is sufficient to clear leukemic blasts from the peripheral blood of mice harboring the fusion genes of t(11;17) APL. This is an impor- |
| Starting Page | 3979 |
| Ending Page | 3980 |
| Page Count | 2 |
| File Format | PDF HTM / HTML |
| Alternate Webpage(s) | http://www.jci.org/articles/view/14343/version/1/pdf/render |
| Alternate Webpage(s) | http://dm5migu4zj3pb.cloudfront.net/manuscripts/14000/14343/JCI0114343.pdf |
| PubMed reference number | 11696570v1 |
| Volume Number | 108 |
| Issue Number | 9 |
| Journal | The Journal of clinical investigation |
| Language | English |
| Access Restriction | Open |
| Subject Keyword | Acute Promyelocytic Leukemia Butyrates Cell Nucleus Chromosome Aberrations Co-Repressor Proteins Cor Triatriatum Gene Expression Genes, Reporter Histone Deacetylase Histones Hydroxamic Acids Leukemia, B-Cell Leukemic Blast Count Leukoencephalopathy, Progressive Multifocal Ligands Lysine PML/RARA Fusion Protein Pharmacology Probable Transcription Factor PML Repression, Psychology Retinoic Acid Receptor Small Molecule Tail Transcription Repressor/Corepressor Transcription, Genetic Transcriptional Repression Tretinoin Vorinostat ZBTB16 gene ZBTB16 wt Allele chemical cofactor chimeric protein t(15;17) transferase activity trichostatin A |
| Content Type | Text |
| Resource Type | Article |
