Homeobox A9 (HOXA9) is a gene that encodes a transcription factor, a protein that regulates the activity of other genes. As a master regulator, it is involved in controlling embryonic development, where it helps establish the body’s structure. In adults, HOXA9’s expression is tightly restricted to specific cells, playing a role in maintaining the function of certain tissues. The gene’s precise regulation is necessary, as its misexpression is frequently linked to the development of several human cancers, most notably acute leukemia.
The Homeobox Family and HOXA9’s Role
HOXA9 is a member of the Homeobox (Hox) gene family, a highly conserved group of genes that direct the formation of an organism’s body plan during early development. These genes are organized into four clusters—A, B, C, and D—located on separate chromosomes in mammals, with HOXA9 residing in the A cluster on chromosome 7. Hox genes encode transcription factor proteins that share a defining structural feature known as the homeodomain, a conserved 60-amino-acid sequence that enables the protein to bind directly to specific DNA sequences.
The precise location of the gene within its cluster dictates when and where it is expressed, which in turn determines the identity of cells along the body axis. HOXA9 rarely acts alone; it frequently forms heterodimers with cofactors from the three amino acid loop extension (TALE) family, such as MEIS1 and PBX3. This cooperative binding increases the protein’s specificity and stability, allowing it to precisely target and regulate the expression of a wider range of downstream genes.
HOXA9’s Crucial Role in Blood Cell Production
The normal function of HOXA9 is most pronounced in the process of hematopoiesis, the continuous formation of all blood cellular components. Within the bone marrow, the gene is highly expressed in hematopoietic stem and progenitor cells (HSPCs), the undifferentiated cells that give rise to all mature blood cell types. HOXA9 acts as a promoter of stem cell self-renewal, helping to maintain the necessary pool of precursor cells.
As HSPCs mature into specialized cells, the expression of the HOXA9 gene is naturally downregulated. This decrease in HOXA9 is a necessary biological switch that permits the cells to exit the self-renewal phase and begin differentiation. Mouse models lacking the HOXA9 gene exhibit defects in this process, showing a measurable reduction in total leukocytes and lymphocytes. The gene’s precise expression levels are integral to ensuring a steady and balanced output of mature blood cells.
When Regulation Fails: HOXA9 and Leukemia
The dysregulation of the HOXA9 gene is a driver in the development of aggressive leukemias, particularly Acute Myeloid Leukemia (AML). In healthy cells, the gene is tightly controlled, but various genetic alterations can lead to its persistent, high-level expression. This oncogenic overexpression is found in a large proportion of AML cases, often exceeding 70%, and is strongly associated with a poor prognosis for patients.
The most common cause of this dysregulation is the Mixed Lineage Leukemia (MLL, also known as KMT2A) gene rearrangement, where a segment of the MLL gene fuses with a partner gene, such as AF9. The resulting MLL fusion protein acts as a potent transcriptional activator, driving the excessive expression of HOXA9, along with its cofactors like MEIS1. Another event is the NUP98-HOXA9 fusion, a direct translocation where the HOXA9 gene fuses with the NUP98 gene, resulting in a chimeric protein. In all these scenarios, regulatory failure causes hematopoietic progenitor cells to become locked in an immature, rapidly proliferating state. They lose the ability to differentiate into functional blood cells, leading to the accumulation of non-functional blast cells.
Targeting HOXA9 in Medical Research
Because the sustained, high-level expression of HOXA9 is required for the survival and proliferation of many aggressive leukemias, the gene represents a therapeutic target. Current research efforts focus on indirectly disrupting the machinery that drives HOXA9 overexpression or targeting the cofactors that enable its oncogenic activity. One promising strategy involves small molecule inhibitors that target members of the MLL fusion protein complex, which is responsible for pathologically activating the HOXA9 gene.
Specifically, research is focused on inhibitors of DOT1L, a histone methyltransferase, and Menin, a scaffolding protein. Both are recruited by the MLL fusion protein to the HOXA9 locus to activate its expression. Disrupting the MLL-Menin interaction, for instance, has shown efficacy in preclinical models by reducing HOXA9 levels and inducing differentiation in leukemia cells. Targeting cofactors is also a major avenue, as the oncogenic potential of HOXA9 is enhanced by its partnership with MEIS1. Inhibiting the function of these cofactors is designed to dismantle the leukemic transcriptional program orchestrated by HOXA9.