Prescription for transcription (original) (raw)

Therapeutic strategies

Nature Reviews Cancer volume 1, page 178 (2001)Cite this article

Acute promyelocytic leukaemia (APL) — a cancer that is characterized by the accumulation of promyelocytic cells in the bone marrow — is associated with translocations involving chromosome 17 that disrupt the gene for retinoic acid receptor-α (RARα). Binding to retinoic acid (RA) changes the function of RARα from a transcriptional repressor to a transcriptional activator, but these translocations create fusion proteins that are trapped in repressor mode. In the November issue of the Journal of Clinical Investigation, Li-Zhen He et al. describe a family of drugs that restore the ability of RARα fusion proteins to activate transcription and also induce remission in a mouse model of APL.

In the absence of RA, corepressors bind to RAR, recruiting histone deacetylases (HDACs) that modify chromatin and block transcription. In the presence of RA, the corepressor complex dissociates. RARα then upregulates genes — the products of which induce growth arrest and terminal differentiation in many cell types, including myeloid haematopoietic cells. In fact, RA is currently used to treat the most common type of APL.

APL-associated fusion proteins such as PML–RARα and PLZF–RARα form stable complexes with HDACs and can only repress transcription. But HDAC inhibitors had been previously shown to block repression of reporter genes by PLZF–RARα. So, could they be used to treat APL?

The authors examined the effects an HDAC inhibitor — known as suberoylanilide hydroxamic acid (SAHA) — on cells from an RA-responsive APL patient and on blasts from a transgenic mouse model of RA-resistant cancer. They found that SAHA treatment induced apoptosis and cell-cycle arrest in both cell types, and that RA-induced differentiation was potentiated by SAHA treatment. Treatment with both drugs also cleared leukaemic blasts from the peripheral blood of the transgenic mice, increasing survival time, whereas treatment with either drug alone did not lead to disease remission. The authors believe that SAHA might sensitize cells to the differentiating effects of RA.

SAHA treatment increased bulk histone acetylation in mice but, as Jonathan Licht points out in an accompanying commentary, the authors did not determine whether SAHA affected chromatin configuration near RAR target genes. SAHA did, however, potentiate RA–dependent transcriptional activation of known RAR target genes. Further research is required to see if SAHA acts directly on APL-associated fusion proteins, or through some other mechanism — such as acetylation of non-histone proteins involved in apoptosis signalling — to stop the spread of cancer cells.

References

ORIGINAL RESEARCH PAPER

  1. He, L.-Z., et al. Histone deacetylase inhibitors induce remission in transgenic models of therapy-resistant acute promyelocytic leukemia. J Clin Invest 108, 1321–1330 (2001) http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11696577&dopt=Abstract
    Article CAS Google Scholar

FURTHER READING

  1. Licht, J. D. Targeting aberrant transcriptional repression in leukemia: a therapeutic reality? J Clin Invest 108,1277–1278 (2001) http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11696570&dopt=Abstract
    Article CAS Google Scholar
  2. Altucci, L. & Gronemeyer, H. The promise of retinoids to fight against cancer. Nature Rev. Cancer 1, 181–193 (2001)| Article |
    Article CAS Google Scholar
  3. Marks, P. A. Histone deacetylases and cancer: causes and therapies. Nature Rev. Cancer 1, 194–202 (2001)
    Article CAS Google Scholar

Download references

Authors

  1. Kristine Novak
    You can also search for this author inPubMed Google Scholar

Rights and permissions

About this article

Cite this article

Novak, K. Prescription for transcription.Nat Rev Cancer 1, 178 (2001). https://doi.org/10.1038/35106030

Download citation