Deregulation of the HOXA9/MEIS1 axis in acute leukemia

Abstract

Purpose of review: HOXA9 is a homeodomain transcription factor that plays an essential role in normal hematopoiesis and acute leukemia, in which its overexpression is strongly correlated with poor prognosis. The present review highlights recent advances in the understanding of genetic alterations leading to deregulation of HOXA9 and the downstream mechanisms of HOXA9-mediated transformation.

Recent findings: A variety of genetic alterations including MLL translocations, NUP98-fusions, NPM1 mutations, CDX deregulation, and MOZ-fusions lead to high-level HOXA9 expression in acute leukemias. The mechanisms resulting in HOXA9 overexpression are beginning to be defined and represent attractive therapeutic targets. Small molecules targeting MLL-fusion protein complex members, such as DOT1L and menin, have shown promising results in animal models, and a DOT1L inhibitor is currently being tested in clinical trials. Essential HOXA9 cofactors and collaborators are also being identified, including transcription factors PU.1 and C/EBPα, which are required for HOXA9-driven leukemia. HOXA9 targets including IGF1, CDX4, INK4A/INK4B/ARF, mir-21, and mir-196b and many others provide another avenue for potential drug development.

Summary: HOXA9 deregulation underlies a large subset of aggressive acute leukemias. Understanding the mechanisms regulating the expression and activity of HOXA9, along with its critical downstream targets, shows promise for the development of more selective and effective leukemia therapies.

Figure 1

Regulation of HOXA9 expression in normal and malignant hematopoiesis. (a) During normal hematopoiesis, HOXA9 is expressed most highly in early progenitor cells and its expression is subsequently down regulated as cells become terminally differentiated. (b) In normal hematopoiesis, HOXA9 expression is regulated by the MLL histone methytransferase, which deposits activating histone 3, lysine 4 trimethylation (H3K4me3) along the HOXA9 locus. This process requires interaction with menin and its cofactor LEDGF. (c) In approximately 50% of acute leukemias, HOXA9 is highly expressed as the result of a variety of upstream genetic alterations. These include MLL1-fusions, NUP98-fusions, MOZ-CBP fusions, NPM1c mutations and ASXL1 mutations. In the case of MLL1-fusions, one of 60 translocations partners is fused to the C-terminus of MLL, resulting in recruitment of the SEC (including DOT1L) and PTEF-b complexes. DOT1L is responsible for depositing activating histone 3 lysine 79 methylation, leading to high HOXA9 expression and malignant transformation. The other genetic abnormalities also result in high HOXA9 expression, though the mechanisms are less well understood.

Figure 2

Model for HOXA9-mediated leukemogenesis. (a) A variety of upstream genetic abnormalities are associated with high expression of HOXA9 and its cofactor MEIS1, both of which are known to play an essential role in acute leukemias. (b) HOXA9 and MEIS1 promote malignant transformation through binding at cis-regulatory elements throughout the genome, whereby they activate and repress downstream gene expression. The targeting and stabilization of HOXA9/MEIS1 at specific loci is likely mediated by cell-type specific collaborator proteins, such as PU.1 and C/EBPα. Upon binding at loci along with the additional cofactor PBX3, HOXA9/MEIS1 recruit coactivating and corepressing histone modifying complexes, such as CREB1/CBP and EZH2 respectively. Recently established activated targets include IGF-1, CDX4, mir-21 and mir-196b. Recently established repressed targets include INK4A, INK4B and ARF.