THERAPEUTIC TARGETING OF TRANSCRIPTION IN ACUTE PROMYELOCYTIC LEUKEMIA BY USE OF AN INHIBITOR OF HISTONE DEACETYLASE

Background: Acetylation of DNA-associated histones is linked to activa tion of gene transcription, whereas histone deacetylation is associate d with transcriptional repression. Recent studies have shown that inhi bitors of histone deacetylases can relieve transcriptional repression caused by the products of certain oncogenes, We tested whether these f indings could be applied clinically to a patient with highly resistant acute promyelocytic leukemia. Methods: A patient who had experienced multiple relapses was treated with all-trans-retinoic acid alone and i n combination with sodium phenylbutyrate, an inhibitor of histone deac etylases. Immunohistochemistry and western blot analysis were used to assay for histone hyperacetylation in mononuclear cells from the patie nt's blood and bone marrow. Marrow mononuclear cells and reverse trans cription-polymerase chain reaction (RT-PCR) analysis of messenger RNA encoded by the PML/RAR-alpha oncogene were used to assess minimal resi dual disease. Results: The patient proved clinically resistant to trea tment with all-trans-retinoic acid alone. However, 23 days after sodiu m phenylbutyrate was added to the treatment regimen, visible leukemic cells had been eliminated from her bone marrow, and she achieved a com plete clinical and cytogenetic remission shortly thereafter. With a se cond treatment course, analysis for minimal residual disease by RT-PCR proved negative, Immunofluorescence and western blot analysis showed that phenylbutyrate caused a time-dependent increase in histone acetyl ation in blood and bone marrow mononuclear cells. Conclusions: Clinica l treatment with an inhibitor of histone deacetylase induces histone h yperacetylation in target cells and may restore sensitivity to the ant i-leukemic effects of all-trans-retinoic acid in acute promyelocytic l eukemia. Similar therapy may prove useful in other neoplastic diseases that are associated with oncogenic repression of gene transcription d ue to recruitment of histone deacetylases.