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Gene Review

Hoxa9  -  homeobox A9

Mus musculus

Synonyms: D6a9, Homeobox protein Hox-1.7, Homeobox protein Hox-A9, Hox-1.7, Hoxa-9
 
 
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Disease relevance of Hoxa9

  • The Hoxa9 and Meis1 genes represent important oncogenic collaborators activated in a significant proportion of human leukemias with genetic alterations in the MLL gene [1].
  • As Pbx proteins are Hox cofactors, which cooperatively bind DNA with Hox proteins to modulate the otherwise similar DNA bind specificities of Hox proteins, these results suggested that Meis1 may function as a cofactor for Hoxa7 and Hoxa9 in the induction of murine myeloid leukemias [2].
  • Conversely, Hoxa9(-/-) mice displayed marked lymphopenia and substantial reductions of common lymphoid progenitors (CLPs) and lymphoid precursors, in addition to significant reductions of common myeloid progenitors (CMPs) and granulocyte/monocyte progenitors (GMPs) [3].
  • A new murine homeo-box, called Hox-1.7, has been identified in a rare cDNA from F9 teratocarcinoma stem cells [4].
  • However, sublethally irradiated Hoxa-9-/- mice develop persistent pancytopenia, indicating unusual sensitivity to ionizing irradiation [5].
 

High impact information on Hoxa9

 

Biological context of Hoxa9

  • The leukemia in the mice lacking Hoxa9 generally displayed a more immature myeloid phenotype than that in the mice that were wild-type for Hoxa9 [8].
  • Hoxa9 influences the phenotype but not the incidence of Mll-AF9 fusion gene leukemia [8].
  • The expression of Meis1 (a novel Pbx-related homeobox gene) and either Hoxa7 or Hoxa9 are coactivated by retroviral integration in BXH2 murine myeloid leukemias (T Nakamura, DA Largaespada, JD Shaughnessy Jr, NA Jenkins and NG Copeland (1996) Nature Genet. 12: 149-153) [2].
  • Therefore, Hoxa9 evokes a cytokine-selective block in differentiation by a mechanism that does not require Meis gene expression or interaction with Pbx through the PIM [9].
  • In addition, overexpression of Hoxa9 in more mature cells enhanced granulopoiesis and partially blocked B lymphopoiesis at the pre-B-cell stage but had no detectable effect on T lymphoid development [10].
 

Anatomical context of Hoxa9

 

Associations of Hoxa9 with chemical compounds

 

Other interactions of Hoxa9

  • In retroviral transduction/transplantation assays, Hoxa7- and Hoxa9-deficient progenitors remained susceptible to transformation by MLL-GAS7, which activates MLL through a dimerization-dependent mechanism [3].
  • It is highly homologous to Hox-1.7 and Hox-3.2, demonstrating extended conservation among three homeo box complexes in the mouse [13].
 

Analytical, diagnostic and therapeutic context of Hoxa9

  • Arrays identified c-Myb and a c-Myb target (Gstm1) among the genes with the strongest response to Hoxa9/Meis1. c-Myb overexpression was verified by Northern blot and quantitative reverse transcription-polymerase chain reaction (RT-PCR) [14].
  • Using gene targeting, we have produced mice with a disruption of Hoxa-9 or Hoxd-9, two paralogous Abdominal B-related genes [15].
  • Sequence analysis revealed that 173bp within the Hoxa-9 ORF was missing from the Hoxa-9T cDNA [16].

References

  1. Molecular dissection of Meis1 reveals 2 domains required for leukemia induction and a key role for Hoxa gene activation. Mamo, A., Krosl, J., Kroon, E., Bijl, J., Thompson, A., Mayotte, N., Girard, S., Bisaillon, R., Beslu, N., Featherstone, M., Sauvageau, G. Blood (2006) [Pubmed]
  2. Identification of a new family of Pbx-related homeobox genes. Nakamura, T., Jenkins, N.A., Copeland, N.G. Oncogene (1996) [Pubmed]
  3. Leukemic transformation of hematopoietic progenitors by MLL-GAS7 in the absence of Hoxa7 or Hoxa9. So, C.W., Karsunky, H., Wong, P., Weissman, I.L., Cleary, M.L. Blood (2004) [Pubmed]
  4. Murine Hox-1.7 homeo-box gene: cloning, chromosomal location, and expression. Rubin, M.R., King, W., Toth, L.E., Sawczuk, I.S., Levine, M.S., D'Eustachio, P., Nguyen-Huu, M.C. Mol. Cell. Biol. (1987) [Pubmed]
  5. Loss of expression of the Hoxa-9 homeobox gene impairs the proliferation and repopulating ability of hematopoietic stem cells. Lawrence, H.J., Christensen, J., Fong, S., Hu, Y.L., Weissman, I., Sauvageau, G., Humphries, R.K., Largman, C. Blood (2005) [Pubmed]
  6. The tumor suppressor menin regulates hematopoiesis and myeloid transformation by influencing Hox gene expression. Chen, Y.X., Yan, J., Keeshan, K., Tubbs, A.T., Wang, H., Silva, A., Brown, E.J., Hess, J.L., Pear, W.S., Hua, X. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  7. Paralogous mouse Hox genes, Hoxa9, Hoxb9, and Hoxd9, function together to control development of the mammary gland in response to pregnancy. Chen, F., Capecchi, M.R. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  8. Hoxa9 influences the phenotype but not the incidence of Mll-AF9 fusion gene leukemia. Kumar, A.R., Hudson, W.A., Chen, W., Nishiuchi, R., Yao, Q., Kersey, J.H. Blood (2004) [Pubmed]
  9. Hoxa9 immortalizes a granulocyte-macrophage colony-stimulating factor-dependent promyelocyte capable of biphenotypic differentiation to neutrophils or macrophages, independent of enforced meis expression. Calvo, K.R., Sykes, D.B., Pasillas, M., Kamps, M.P. Mol. Cell. Biol. (2000) [Pubmed]
  10. Overexpression of the myeloid leukemia-associated Hoxa9 gene in bone marrow cells induces stem cell expansion. Thorsteinsdottir, U., Mamo, A., Kroon, E., Jerome, L., Bijl, J., Lawrence, H.J., Humphries, K., Sauvageau, G. Blood (2002) [Pubmed]
  11. Inhibition of myeloid differentiation by Hoxa9, Hoxb8, and Meis homeobox genes. Fujino, T., Yamazaki, Y., Largaespada, D.A., Jenkins, N.A., Copeland, N.G., Hirokawa, K., Nakamura, T. Exp. Hematol. (2001) [Pubmed]
  12. Abdominal B (AbdB) Hoxa genes: regulation in adult uterus by estrogen and progesterone and repression in müllerian duct by the synthetic estrogen diethylstilbestrol (DES). Ma, L., Benson, G.V., Lim, H., Dey, S.K., Maas, R.L. Dev. Biol. (1998) [Pubmed]
  13. The developmental expression pattern of a new murine homeo box gene: Hox-2.5. Bogarad, L.D., Utset, M.F., Awgulewitsch, A., Miki, T., Hart, C.P., Ruddle, F.H. Dev. Biol. (1989) [Pubmed]
  14. c-Myb is an essential downstream target for homeobox-mediated transformation of hematopoietic cells. Hess, J.L., Bittner, C.B., Zeisig, D.T., Bach, C., Fuchs, U., Borkhardt, A., Frampton, J., Slany, R.K. Blood (2006) [Pubmed]
  15. Specific and redundant functions of the paralogous Hoxa-9 and Hoxd-9 genes in forelimb and axial skeleton patterning. Fromental-Ramain, C., Warot, X., Lakkaraju, S., Favier, B., Haack, H., Birling, C., Dierich, A., Doll e, P., Chambon, P. Development (1996) [Pubmed]
  16. Analysis of the murine Hoxa-9 cDNA: an alternatively spliced transcript encodes a truncated protein lacking the homeodomain. Fujimoto, S., Araki, K., Chisaka, O., Araki, M., Takagi, K., Yamamura, K. Gene (1998) [Pubmed]
 
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