Predicting the effect of transcription therapy in hematologic malignancies
Molecular lesions of genes encoding for transcriptional regulatory proteins are common oncogenic events in hematologic malignancies. Transcriptional activation and repression both occur by virtue of the choreographed recruitment of multisubunit cofactor complexes to target gene loci. As a consequence, the three-dimensional structure of the target gene is altered and its potential to support transcription is increased or decreased. The complexity of the transcriptional process offers a rich substrate for designing therapeutic agents. The objective of such 'transcription therapy' is to regain control over cohorts of target genes and restore the normal genetic and epigenetic programming of the cancer cell. The success of all-trans retinoic acid in the treatment of acute promyelocytic leukemia indicates that transcription therapy can be highly effective and safe. A classification scheme of these therapeutic strategies is proposed herein, which allows predictions to be made regarding specificity, efficacy, disease spectrum and side effects. This framework could help facilitate discussion of the mechanisms of action of transcription therapy drugs as well as the design of preclinical and clinical trials in the future.