Regulation of HOX gene expression in AML

Abstract

As key developmental regulators, HOX cluster genes have varied and context-specific roles in normal and malignant hematopoiesis. A complex interaction of transcription factors, epigenetic regulators, long non-coding RNAs and chromatin structural changes orchestrate HOX expression in leukemia cells. In this review we summarize molecular mechanisms underlying HOX regulation in clinical subsets of AML, with a focus on NPM1 mutated (NPM1^mut) AML comprising a third of all AML patients. While the leukemia initiating function of the NPM1 mutation is clearly dependent on HOX activity, the favorable treatment responses in these patients with upregulation of HOX cluster genes is a poorly understood paradoxical observation. Recent data confirm FOXM1 as a suppressor of HOX activity and a well-known binding partner of NPM suggesting that FOXM1 inactivation may mediate the effect of cytoplasmic NPM on HOX upregulation. Conversely the residual nuclear fraction of mutant NPM has also been recently shown to have chromatin modifying effects permissive to HOX expression. Recent identification of the menin-MLL interaction as a critical vulnerability of HOX-dependent AML has fueled the development of menin inhibitors that are clinically active in NPM1 and MLL rearranged AML despite inconsistent suppression of the HOX locus. Insights into context-specific regulation of HOX in AML may provide a solid foundation for targeting this common vulnerability across several major AML subtypes.

Fig. 1. General and context-specific mechanisms of HOX regulation in AML.

A Major mechanisms of regulation of expression of HOX A/B genes in human leukemia cells include (i) cytogenetic rearrangements resulting in novel fusion proteins, (ii) long non-coding RNA association with the HOX gene locus and (iii) binding of upstream protein such as CDX proteins. B Regulation of HOX A in the context of NPM1^mut AML includes two discrete mechanisms whereby (i) residual nuclear mutant NPM1 directly binds to chromatin and hijacks the transcriptional complex (RNA Pol II, MLL-Menin and super elongation complex) and (ii) the bulk of mutant NPM1 sequesters and relocalizes to the cytoplasm several repressors of HOX gene expression including FOXM1, and PU.1. * Additional cytogenetic arrangements inducing HOX expression include NUP98-NSD1, SET -NUP214, DEK-NUP214.