Role of HOXA9 in leukemia: dysregulation, cofactors and essential targets

Abstract

HOXA9 is a homeodomain-containing transcription factor that has an important role in hematopoietic stem cell expansion and is commonly deregulated in acute leukemias. A variety of upstream genetic alterations in acute myeloid leukemia lead to overexpression of HOXA9, which is a strong predictor of poor prognosis. In many cases, HOXA9 has been shown to be necessary for maintaining leukemic transformation; however, the molecular mechanisms through which it promotes leukemogenesis remain elusive. Recent work has established that HOXA9 regulates downstream gene expression through binding at promoter distal enhancers along with a subset of cell-specific cofactor and collaborator proteins. Increasing efforts are being made to identify both the critical cofactors and target genes required for maintaining transformation in HOXA9-overexpressing leukemias. With continued advances in understanding HOXA9-mediated transformation, there is a wealth of opportunity for developing novel therapeutics that would be applicable for greater than 50% of AML with overexpression of HOXA9.

Figure 1

HOXA9 regulation in normal hematopoiesis and leukemia. (A) During development and hematopoiesis, expression of HOXA9 is primarily regulated by the antagonistic actions of the MLL complex and polycomb repressive complex. These histone methytransferases deposit the activating H3K4me3 and repressive H3K27me3 marks respectively. CDX proteins also play a role in HOXA9 regulation, through mechanisms that are not well defined. (B) A variety of upstream genetic alterations lead to the up regulation of HOXA9, which is essential for the acute leukemias that result from these alterations. Decreased expression of EZH2 and chromosomal translocations leading to MLL-fusion proteins result in activation of HOXA9 expression through dysregulated chromatin modification. Cytoplasmic mutations of NPM1, fusion proteins with NUP98 and overexpression of CDX2 and CDX4 also leads to up regulation of HOXA9 through mechanisms that remain to be completely defined. HOXA9 likely goes on to promote transformation through the activation of proproliferative genes and the repression of genes required for cellular differentiation.