Upregulation of Meis1 and HoxA9 in acute lymphocytic leukemias with the t(4 : 11) abnormality

Rearrangements of the human ALL-1 gene are frequently encountered in acute lymphocytic leukemias (ALL) and acute myeloid leukemias (AML), These rearra ngements are mostly due to chromosome translocations and result in producti on of chimeric proteins composed of the N-terminal fragment of ALL-1 and th e C-terminal segments of the partner proteins. The most common chromosome t ranslocation involving ALL-I is the t(4:11) associated with ALL. ALL-1 is t he human homologue of Drosophila trithorax and directly activates transcrip tion of multiple Hox genes. A preliminary DNA microarray screen indicated t hat the Meis1, HoxA9 and AC133 genes were overexpressed in ALLs with t(4:11 ), compared to ALLs with very similar phenotype but without the chromosomal abnormality. These genes, as well as additional five Hox genes, were subje cted to comprehensive semi-quantitative or quantitative RT-PCR analysis in 57 primary ALL and AML tumors. Meis1 and HoxA9 were found expressed in 13/1 4 of ALLs with the t(4:11) and in 8/8 of AMLs with ALL-1 rearrangements. Th e two genes were not consistently transcribed in other types of ALL, AC133 was transcribed in 13/14 of ALLs with t(4:11), but in only 4/8 of AMLs with ALL-1 rearrangements. HoxA10 was expressed in most leukemias with ALL-1 al terations, but was also transcribed in PrePreB CD10(-) ALLs lacking the t(4 : 11). Expression of HoxA5, HoxA7, HoxC8 and HoxC10 did not correlate with ALL-1 rearrangements. Coexpression of Meis1 and HoxA9, overexpression of H oxA10, and overexpression or fusion of HoxA9 were previously implicated in certain acute myeloid leukemias in mice and humans. The present work sugges ts that upregulation of Meis1, HoxA9, and possibly HoxA10 might also play a role in pathogenesis of acute lymphocytic and acute myeloid leukemias asso ciated with ALL-1 fusions.