The homeobox (HOX) genes are a highly conserved family of transcription factors involved in early development to control the body plan of an embryo, as well as adult processes including hematopoiesis. Deregulated expression of HOX genes, due to specific chromosomal translocations, has been identified in different subtypes of leukemia. Recently, we completed a detailed genomic analysis on acute megakaryoblastic leukemia (AMKL), and identified novel fusions involving a HOX cluster gene (HOXr). The fusion events involving HOX genes were varied, with the majority predicted to lead to an in-frame functional fusion protein. Several fusions identified in our sequencing studies, however, involve non-coding RNA species and are predicted to result in a loss of function of these regulatory transcripts. To study the role of HOXr we will determine the ability of non-coding RNA chimeric transcripts involving HOX antisense genes to regulate nearby HOX genes. Furthermore, we will assess whether co-introduction of a HOXr and activating mutation in the MPL gene accelerates the development of leukemia in a murine model. Additionally, these HOX fusion events are thus far restricted to pediatric cases. Therefore, we aim to identify novel HOX fusion events in other adult and pediatric leukemia cases and evaluate their clinical outcome. This work is performed in collaboration with prof. dr. Michel Zwaan (Princess Máxima Center), and prof. dr. Tanja Gruber (St. Jude Children’s Research Hospital, Memphis, USA).