Biology and treatment of acute progranulocytic leukemia.
Acute progranulocytic leukemia (APL) is one of the most curable of all human cancers. Combination treatment with retinoic acid (RA) and anthracycline-based chemotherapy is safe and effective for the vast majority of patients, and several novel treatment approaches are under investigation for high-risk or relapsed patients. The APL-specific oncogenes PML-RAR alpha and PLZF-RAR alpha both bind nuclear corepressors and recruit histone deacetylase activity to promoters of RA target genes. The differential sensitivity of binding of these oncogenes to nuclear corepressors in the presence of RA appears to explain the resistance of PLZF-RAR alpha-related APL to RA and at the same time explains the effectiveness of RA in PML-RAR alpha-positive APL. Transcriptional repression of RA target genes, mediated by histone deacetylase activity, may thus be a key pathogenetic event in APL. Cure of the minority of resistant patients requires further refinement of current treatment approaches and appropriately timed incorporation of novel therapies, such as arsenic trioxide or histone deacetylase inhibitors.
Slack
J L
JL
Department of Medicine, Roswell Park Cancer Institute, Buffalo, New York 14263, USA.
D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000235:genetics / Q000473:pathology* / Q000628:therapy*; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism; D014178:Translocation, Genetic
D009363:Neoplasm Proteins; D015514:Oncogene Proteins, Fusion