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HGNC Approved Gene Symbol: HOXA9
Cytogenetic location: 7p15.2 Genomic coordinates (GRCh38): 7:27,162,438-27,165,537 (from NCBI)
In vertebrates, HOX genes exhibit spatially restricted patterns of expression coincident with the morphogenesis of body-segmented structures. The specific combination of HOX genes expressed in a particular segment determines tissue identity. The HOXA9 gene encodes a class I homeodomain protein potentially involved in myeloid differentiation.
Kim et al. (1998) cloned the HOXA9 gene and identified several splice variants. Using exon-specific probes in Northern blot analysis, they detected a 1.8-kb homeobox-containing transcript in all fetal tissues tested (brain, lung, liver, and kidney); 2.2- and 3.3-kb transcripts in fetal and adult kidney and in adult skeletal muscle; and a 1.0-kb transcript in all adult and fetal tissues tested.
Vijapurkar et al. (2004) found that mouse Hoxa9 was phosphorylated by protein kinase C (PKC; see 176960) and more weakly by casein kinase II (see 115440). PKC phosphorylated Hoxa9 on ser204 and thr205, which are located within a highly conserved N-terminal sequence (STRK). PKC phosphorylation on ser204 decreased Hoxa9 DNA binding affinity in vitro and blocked formation of DNA-binding complexes between endogenous HOXA9 and PBX (176310) in a human hematopoietic cell line. Phorbol ester induction of myeloid cell differentiation correlated with phosphorylation of HOXA9 on ser204 and the loss of in vivo DNA binding activity, suggesting that PKC regulates the role of HOXA9 in myeloid cell proliferation and differentiation.
Cheng et al. (2005) found that HOX genes, which normally regulate mullerian duct differentiation, are not expressed in normal ovarian surface epithelium, but are expressed in epithelial ovarian cancer subtypes according to the pattern of mullerian-like differentiation of the cancers. Ectopic expression of Hoxa9 in tumorigenic mouse ovarian surface epithelial cells gave rise to papillary tumors resembling serous ovarian cancers. In contrast, Hoxa10 (142957) and Hoxa11 (142958) induced morphogenesis of endometrioid-like and mucinous-like tumors, respectively. Hoxa7 (142950) showed no lineage specificity, but promoted the abilities of Hoxa9, Hoxa10, and Hoxa11 to induce differentiation along their respective pathways.
Xue et al. (2015) uncovered unique RNA regulons embedded in homeobox (HOX) 5-prime UTRs that confer ribosome-mediated control of gene expression. These structured RNA elements, resembling viral internal ribosome entry sites (IRESs), are found in subsets of HOX mRNAs. They facilitate ribosome recruitment and require the ribosomal protein RPL38 (604182) for their activity. Despite numerous layers of HOX gene regulation, these IRES elements are essential for converting HOX transcripts into proteins to pattern the mammalian body plan. This specialized mode of IRES-dependent translation is enabled by an additional regulatory element that the authors called the translation inhibitory element (TIE), which blocks cap-dependent translation of transcripts. Xue et al. (2015) concluded that these data uncovered a new paradigm for ribosome-mediated control of gene expression and organismal development. Xue et al. (2015) found that the Hoxa9 IRES is required for axial skeleton patterning but not for Hoxa9 mRNA expression in mouse, and that the Hoxa9 IRES is critical for Hoxa9 translation in vivo.
Schworer et al. (2016) showed that the epigenetic stress response in muscle stem cells (also known as satellite cells) differs between aged and young mice. The alteration includes aberrant global and site-specific induction of active chromatin marks in activated satellite cells from aged mice, resulting in the specific induction of Hoxa9 but not other Hox genes. Hoxa9 in turn activates several developmental pathways and represents a decisive factor that separates satellite cell gene expression in aged mice from that in young mice. The activated pathways included most inhibitors of satellite cell function in aging muscle, including Wnt (see WNT1, 164820), TGF-beta (190180), JAK/STAT (see 600555), and senescence signaling. Inhibition of aberrant chromatin activation or deletion of Hoxa9 improves satellite cell function and muscle regeneration in aged mice, whereas overexpression of Hoxa9 mimics aging-associated defects in satellite cells from young mice, which can be rescued by the inhibition of Hoxa9-targeted developmental pathways. Together, these data delineated an altered epigenetic stress response in activated satellite cells from aged mice, which limits satellite cell function and muscle regeneration by Hoxa9-dependent activation of developmental pathways.
Kim et al. (1998) determined that the HOXA9 gene contains 3 exons and spans about 7.2 kb. The upstream region contains 2 TATA boxes, a CAAT box, a GC box, and body segmentation-specific factor-binding sites. A CpG island and 2 retinoic acid response elements (RAREs) are located within intron 1.
By genomic sequence analysis, Kim et al. (1998) mapped the HOXA9 gene to chromosome 7p15.
HOXA9/NUP98 Fusion Gene
Expression of Hoxa7 (142950) and Hoxa9 is activated by proviral integration in BXH2 murine myeloid leukemias. This result, combined with the mapping of the HOXA cluster to 7p15, suggested that one of the HOXA genes may be involved in the human t(7;11)(p15;p15) translocation found in some myeloid leukemia patients. Nakamura et al. (1996) showed that in 3 patients with t(7;11), the chromosome rearrangement created a genomic fusion between the HOXA9 gene and the nucleoporin gene NUP98 (601021), a member of the GLFG nucleoporin family, on 11p15. The translocation produced an invariant chimeric NUP98/HOXA9 transcript containing the N-terminal half of NUP98 fused in-frame to HOXA9. These studies identified HOXA9 as an important human myeloid leukemia gene and suggested an important role for nucleoporins in human myeloid leukemia, given that a second nucleoporin, NUP214 (114350), has also been implicated in human myeloid leukemia.
Borrow et al. (1996) likewise identified the HOXA9 and NUP98 genes as the parents of the fusion in t(7;11)(p15;p15) in acute myeloid leukemia of the FABM2 and M4 types. They suggested that the predicted NUP98/HOXA9 fusion protein may promote leukemogenesis through inhibition of HOXA9-mediated terminal differentiation and/or aberrant nucleocytoplasmic transport.
Ghannam et al. (2004) expressed a NUP98/HOXA9 fusion plasmid in human K562 myeloid leukemia cells. Microarray analysis revealed that the aberrant transcription factor had stronger and wider transcriptional effect than HOXA9 alone; NUP98 itself had no transcriptional activity. Ghannam et al. (2004) concluded that NUP98/HOXA9 requires the DNA-binding domain of HOXA9 for its activity.
Barr (1996) provided a table listing 9 types of gene fusions occurring in myeloid leukemia.
HOXA9/MSI2 Fusion Gene
Barbouti et al. (2003) identified a cryptic balanced translocation in a chronic myeloid leukemia patient whose disease had progressed to the accelerated phase and blast crisis. The translocation, t(7;17)(p15;q23), resulted in a chimeric gene that fused exon 9 of MSI2 (607897) in-frame with the intermediate exon (exon 1b) of HOXA9. The fusion protein retained the 2 intact RRM domains of MSI2 fused to the homeobox domain of HOXA9. The reciprocal HOXA9/MSI2 chimeric protein was not detected.
Barbouti, A., Hoglund, M., Johansson, B., Lassen, C., Nilsson, P.-G., Hagemeijer, A., Mitelman, F., Fioretos, T. A novel gene, MSI2, encoding a putative RNA-binding protein is recurrently rearranged at disease progression of chronic myeloid leukemia and forms a fusion gene with HOXA9 as a result of the cryptic t(7;17)(p15;q23). Cancer Res. 63: 1202-1206, 2003. [PubMed: 12649177]
Barr, F. G. The malevolence of matchmaking. Nature Genet. 12: 113-114, 1996. [PubMed: 8563741] [Full Text: https://doi.org/10.1038/ng0296-113]
Borrow, J., Shearman, A. M., Stanton, V. P., Jr., Becher, R., Collins, T., Williams, A. J., Dube, I., Katz, F., Kwong, Y. L., Morris, C., Ohyashiki, K., Toyama, K., Rowley, J., Housman, D. E. The t(7;11)(p15;p15) translocation in acute myeloid leukaemia fuses the genes for nucleoporin NUP98 and class I homeoprotein HOXA9. Nature Genet. 12: 159-167, 1996. [PubMed: 8563754] [Full Text: https://doi.org/10.1038/ng0296-159]
Cheng, W., Liu, J., Yoshida, H., Rosen, D., Naora, H. Lineage infidelity of epithelial ovarian cancers is controlled by HOX genes that specify regional identity in the reproductive tract. Nature Med. 11: 531-537, 2005. [PubMed: 15821746] [Full Text: https://doi.org/10.1038/nm1230]
Ghannam, G., Takeda, A., Camarata, T., Moore, M. A., Viale, A., Yaseen, N. R. The oncogene Nup98-HOXA9 induces gene transcription in myeloid cells. J. Biol. Chem. 279: 866-875, 2004. [PubMed: 14561764] [Full Text: https://doi.org/10.1074/jbc.M307280200]
Kim, M. H., Chang, H.-H., Shin, C., Cho, M., Park, D., Park, H. W. Genomic structure and sequence analysis of human HOXA-9. DNA Cell Biol. 17: 407-414, 1998. [PubMed: 9628584] [Full Text: https://doi.org/10.1089/dna.1998.17.407]
Nakamura, T., Largaespada, D. A., Lee, M. P., Johnson, L. A., Ohyashiki, K., Toyama, K., Chen, S. J., Willman, C. L., Chen, I.-M., Feinberg, A. P., Jenkins, N. A., Copeland, N. G., Shaughnessy, J. D., Jr. Fusion of the nucleoporin gene NUP98 to HOXA9 by the chromosome translocation t(7;11)(p15;p15) in human myeloid leukaemia. Nature Genet. 12: 154-158, 1996. [PubMed: 8563753] [Full Text: https://doi.org/10.1038/ng0296-154]
Schworer, S., Becker, F., Feller, C., Baig, A. H., Kober, U., Henze, H., Kraus, J. M., Xin, B., Lechel, A., Lipka, D. B., Varghese, C. S., Schmidt, M., Rohs, R., Aebersold, R., Medina, K. L., Kestler, H. A., Neri, F., von Maltzahn, J., Tumpel, S., Rudolph, K. L. Epigenetic stress responses induce muscle stem-cell ageing by Hoxa9 developmental signals. Nature 540: 428-432, 2016. Note: Erratum: 572: E11-E15, 2019. [PubMed: 27919074] [Full Text: https://doi.org/10.1038/nature20603]
Vijapurkar, U., Fischbach, N., Shen, W., Brandts, C., Stokoe, D., Lawrence, H. J., Largman, C. Protein kinase C-mediated phosphorylation of the leukemia-associated HOXA9 protein impairs its DNA binding ability and induces myeloid differentiation. Molec. Cell. Biol. 24: 3827-3837, 2004. [PubMed: 15082777] [Full Text: https://doi.org/10.1128/MCB.24.9.3827-3837.2004]
Xue, S., Tian, S., Fujii, K., Kladwang, W., Das, R., Barna, M. RNA regulons in Hox 5-prime UTRs confer ribosome specificity to gene regulation. Nature 517: 33-38, 2015. [PubMed: 25409156] [Full Text: https://doi.org/10.1038/nature14010]