A growing body of evidence supports the notion that misexpression of the HOXA9 homeobox gene is a common and critical event in myeloid leukemogenesis. Enforced expression of HOXA9 in murine marrow cells is clearly leukemogenic, and the gene is aberrantly upregulated in a large majority of cases of human acute myelogenous leukemia (AML). In a recent survey of 6,800 human genes in acute leukemia, HOXA9 expression was shown to be highly specific for AML and was the single best marker for a poor outcome. The major hypothesis of this grant is that aberrant activation of HOXA9 is a frequent downstream consequence of many, if not most, oncogenic events that lead to AML, and that this activation is critical to the induction and maintenance of the malignant phenotype. An additional key hypothesis is that HOXA9 overexpression contributes to the drug resistance phenotype. The focus of this application is to explore strategies to inhibit HOXA9 expression and/or function as a novel therapeutic approach for AML. This project has 3 major aims: i) to test the in vitra biologic effects of over-expression of HOXA9 in a factor-dependent nonleukemogenic myeloid cell line engineered to express high levels of HOXA9 in a tetracycline-regulatable manner, and to use this inducible cell line model to test strategies to block HOXA9 expression. ii) to develop an in vivo model of a Tet-regulatable HOXA9-driven AML in mice, which can be used to test treatment the strategies developed in Aim #1 in a whole animal, and iii) to study the ability of anti-HOXA9 strategies to alter the proliferation, differentiation and chemotherapeutic sensitivity of fresh leukemic cells from patients, and of human myeloid leukemic cell lines that show high levels of endogenous HOXA9 expression. The specific strategies to be tested include the use of conventional antisense oligonucleotides, double-stranded DNA decoys, and double-stranded RNA to induce RNA interference. We anticipate that therapies targeting the expression and/or function of HOX proteins could have a major role in the clinical treatment of leukemia.
| Hu, Yu-Long; Passegue, Emmanuelle; Fong, Stephen et al. (2007) Evidence that the Pim1 kinase gene is a direct target of HOXA9. Blood 109:4732-8 |
| Dorsam, Sheri Tinnell; Ferrell, Christina M; Dorsam, Glenn P et al. (2004) The transcriptome of the leukemogenic homeoprotein HOXA9 in human hematopoietic cells. Blood 103:1676-84 |
