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Review
. 2019 Jun 17;11(6):837.
doi: 10.3390/cancers11060837.

Direct and Indirect Targeting of HOXA9 Transcription Factor in Acute Myeloid Leukemia

Mélanie Lambert  1   2 , Meryem Alioui  3   4 , Samy Jambon  5   6 , Sabine Depauw  7   8 , Isabelle Van Seuningen  9 , Marie-Hélène David-Cordonnier  10   11
Affiliations
Review

Direct and Indirect Targeting of HOXA9 Transcription Factor in Acute Myeloid Leukemia

Mélanie Lambert et al. Cancers (Basel). .

Abstract

HOXA9 (Homeobox A9) is a homeotic transcription factor known for more than two decades to be associated with leukemia. The expression of HOXA9 homeoprotein is associated with anterior-posterior patterning during embryonic development, and its expression is then abolished in most adult cells, with the exception of hematopoietic progenitor cells. The oncogenic function of HOXA9 was first assessed in human acute myeloid leukemia (AML), particularly in the mixed-phenotype associated lineage leukemia (MPAL) subtype. HOXA9 expression in AML is associated with aggressiveness and a poor prognosis. Since then, HOXA9 has been involved in other hematopoietic malignancies and an increasing number of solid tumors. Despite this, HOXA9 was for a long time not targeted to treat cancer, mainly since, as a transcription factor, it belongs to a class of protein long considered to be an "undruggable" target; however, things have now evolved. The aim of the present review is to focus on the different aspects of HOXA9 targeting that could be achieved through multiple ways: (1) indirectly, through the inhibition of its expression, a strategy acting principally at the epigenetic level; or (2) directly, through the inhibition of its transcription factor function by acting at either the protein/protein interaction or the protein/DNA interaction interfaces.

Keywords: HOXA9; acute myeloid leukemia; epigenetic; protein/DNA interaction inhibitors; protein/protein interaction inhibitors; transcription factor.

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Conflict of interest statement

The authors declare no conflict of interest

Figures

Figure 1
Figure 1
The different modes of regulation of HOXA9 expression and function in acute myeloid leukemia (AML). BRD4, bromodomain-related protein 4; CBP, CREB-binding protein; CDK9, cyclin-dependent kinase 9; D-2-HG, D-2-hydroxyglutarate; DHODH, dihydroorotate dehydrogenase; DNMT3A, DNA methyl transferase 3A; DOT1L, disruptor of telomeric silencing 1-like protein; HDAC, histone deacetylase; HEXIM1, hexamethylene bisacetamide (HMBA) inducible protein 1; HOXA9, homeobox A9; IDH, isocitrate dehydrogenase; KDM4C/lysine-specific demethylase 4C; LEDGF, lens epithelium-derived growth factor; LSD1, lysine-specific demethylase 1; MEIS1, myeloid ecotropic viral integration site 1; MLL, mixed lineage leukemia; MOF, males absent on the first; NPM1, nucleophosmin 1; NSD1, nuclear receptor binding SET domain protein 1; NUP98, nucleoporin 98kDa; PBX3, pre-B-cell leukemia transcription factor 3; PRMT1, protein arginine N-methyltransferase 1; pTEFb, positive transcription elongation factor b; SMAD4, mothers against decapentaplegic homolog 4; WDR5, WD repeat protein 5; XPO-1, exportin-1.
Figure 2
Figure 2
Indirect targeting of HOXA9 expression in AML: multiple epigenetic and non-epigenetic therapeutic opportunities.
Figure 3
Figure 3
Direct targeting of HOXA9 function: inhibition of protein/protein or protein/DNA interaction to block HOXA9 transcriptional activity in AML.
See this image and copyright information in PMC

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