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). 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. By DNA cross-hybridization we have identified two Meis1-related genes, Meis2 and Meis3. Sequence analysis revealed extensive amino acid similarity among the three Meis proteins both within and outside of the homeodomain. Phylogenetic analysis showed that the Meis genes belong to a distinct family of Pbx-related genes. Chromosome mapping studies indicated that Meis2 and Meis3 are unlinked to Meis1 and map to mouse chromosome 2 and 7, respectively. The Meis genes displayed distinct but overlapping patterns of expression in normal tissues and were expressed in some cases of murine myeloid leukemia. The identification of two additional Meis genes identifies a new family of potential Hox cofactors as well as two new potential disease genes.