Chromosomal rearrangements of the mixed lineage leukemia (MLL) gene, which result in expression of MLL-fusion proteins, occur in 5-10% of both acute myeloid leukemia and acute lymphoid leukemia. 1 MLL leukemia patients have very unfavorable prognoses, 1, 2 emphasizing the need for new therapies. The MLL-fusion proteins retain the N-terminal portion of MLL fused with 1 of> 70 different fusion partners, classified based on their cellular localization as nuclear and cytoplasmic proteins. 3, 4 It has been proposed that molecular mechanism of transformation used by different MLL fusions is dependent on the type of fusion partner. 4 The MLL fusions harboring nuclear fusion partners (for example, AF4, AF9, ENL, AF10, ELL) are frequently associated with transcriptional elongation complexes leading to transcriptional activation of target genes, while cytoplasmic fusion partners of MLL (for example, AF6, AF1p, GAS7) contain dimerization domains required for transformation. 4, 5 The high diversity of MLL fusion partners raises a question whether it is possible to develop a general therapeutic strategy to block the oncogenic activity of MLL-fusion proteins in a fusion partner-independent manner. The protein menin was shown to directly interact with the N-terminal fragment of MLL retained in all MLL-fusion proteins, and this interaction is critical for the MLL-fusion protein-mediated transformation. 6, 7 Therefore, blocking the menin-MLL interaction could inhibit oncogenic activity of all MLL-fusion proteins, providing a rationale for a general therapeutic strategy for MLL leukemia patients. To address this important question, we