The MLL (mixed lineage leukemia) gene forms chimeric fusions with a diverse set of partner genes as a consequence of chromosome translocations in leukemia. In several fusion partners, a transcriptional activation domain appears to be essential for conferring leukemogenic capacity on MLL protein. Other fusion partners, however, lack such domains. Here we show that gephyrin (GPHN), a neuronal receptor assembly protein and rare fusion partner of MLL in leukemia, has the capacity as an MLL-GPHN chimera to transform hematopoietic progenitors, despite lack of transcriptional activity. A small 15-amino acid tubulin-binding domain of GPHN is necessary and sufficient for this activity in vitro and in vivo. This domain also confers oligomerization capacity on MLL protein, suggesting that such activity may contribute critically to leukemogenesis. The transduction of MLL-GPHN into hematopoietic progenitor cells caused myeloid and lymphoid lineage leukemias in mice, suggesting that MLL-GPHN can target multipotent progenitor cells. Our results, and other recent data, provide a mechanism for oncogenic conversion of MLL by fusion partners encoding cytoplasmic proteins.