We are interested in the identification of the genes involved in the regulation of Hox11(Tlx1). Hox11 is an orphan homeobox gene, which was originally isolated from the recurrent t(10;14)(q24;q11) breakpoint found in human T-cell acute lymphoblastic leukemia (T-ALL). The normal developmental function and regulation of this orphan homeobox gene remains unknown, except for its essential role in spleen development. The expression of Hox11 is a tightly regulated process, controlled by as-yet-unidentified genes. Our central hypothesis is that the identification of the genes that regulate Hox11 will help us to better understand its role in human leukemia. To achieve our goals, we have designed an ENU mutagenesis screen in zebrafish to look for mutations affecting Hox11 expression. Two mutants have already been recovered. The S6 mutant lack Hox11 expression in the spleen primordium and the hindbrain at day 5 postfertilization, while the S9 mutant lacks Hox11 expression only in the spleen primordium. The identification of the genes regulating the expression of Hox11 will not only elucidate the molecular-genetic mechanisms of spleen organogenesis, but will also provide insight into the regulation of this leukemogenic homeobox gene.