Leukaemogenesis: more than mutant genes

Abstract

Acute leukaemias, arising from neoplastic transformation of uncommitted or partially committed haematopoietic stem cells, are characterized by recurring chromosomal aberrations and gene mutations that are crucial to disease pathogenesis. The recurring chromosomal translocations in acute myeloid leukaemia (AML) result in the generation of chimeric fusion proteins that in many cases function as transcriptional regulators. These include AML1–ETO (generated by a translocation between chromosomes 8 and 21, t(8;21)); CBFB–MYH11 (generated by an inversion of chromosome 16, inv(16) or t(16;16)); PML–RARA (generated by t(15;17)); MOZ–CBP (generated by t(8;16)); MORF–CBP (generated by t(10;16)); MOZ–TIF2 (generated by inv(8)); and MLL fused with various partners (generated by t(11q23)). They contribute to leukaemogenesis, at least in part by causing transcriptional deregulation through epigenetic modifications. Epigenetic modifications, including DNA methylation, DNA demethylation and histone changes, lead to the activation or repression of gene expression. Aberrant epigenetic changes occur frequently in acute leukaemias. Fusion genes resulting from chromosome translocations can be regulators or mediators of the epigenetic machinery. MicroRNA (miRNA) regulation may also considerably contribute to leukaemogenesis. Some miRNAs function as oncogenes or tumour suppressor genes in acute leukaemias. miRNA signatures correlate with cytogenetic and molecular subtypes of acute leukaemias, and some miRNA signatures are associated with outcome or survival of acute leukaemias. Not only do miRNAs function in an epigenetic manner by post-transcriptional regulation of target genes, but they can also be targets of the epigenetic machinery and effectors of DNA methylation and histone modifications. These functions might be involved in leukaemogenesis. Although the genetic heterogeneity of acute leukaemias poses therapeutic challenges, drugs or small molecules that target components of the epigenetic machinery hold great promise in the treatment of leukaemias. The use of all-trans retinoic acid in the therapy of acute promyelocytic leukaemia is one of the best known and most successful examples of targeted therapy involved in epigenetic changes; progress has also been made in the clinical trials of histone deacetylase inhibitors and DNA methyltransferase inhibitors. However, more effective treatment strategies are needed.