MLL1 methyltransferase activity mediates MLL1-dependent transcription and MLL cell survival.
Major Finding: MLL1 methyltransferase activity mediates MLL1-dependent transcription and MLL cell survival.
Concept: Disruption of the MLL1–WDR5 interaction inhibits MLL1 activity at MLL1-dependent genes.
Impact: This MLL1 inhibitor can be used to study MLL1 function and may have therapeutic potential.
A subset of acute myeloid leukemia and acute lymphoblastic leukemia is characterized by balanced oncogenic translocations in mixed-lineage leukemia 1 (MLL1), which encodes a histone methyltransferase (HMT) that catalyzes mono-, di- or trimethylation of histone H3 on lysine 4 (H3K4) and is involved in regulating hematopoiesis. Maximum activation of MLL1 requires its assembly into a multiprotein complex that includes WD repeat domain 5 (WDR5), prompting Cao and colleagues to characterize the specificity of MM-401, a peptidomimetic-based compound that exhibits a high binding affinity for WDR5 and disrupts the MLL1–WDR5 interaction. In vitro, MM-401 specifically inhibited the methyltransferase activity of MLL1 but not other histone lysine methyltransferases or MLL family HMTs; the specificity of MM-401 for MLL1 was dependent on the unique requirement of WDR5 for MLL1 complex formation and activation. In line with this, MM-401 treatment resulted in decreased MLL1-regulated H3K4 methylation at HOXA loci and reduced HOX gene expression in the absence of global changes in histone modifications. In addition, MM-401–mediated changes in transcription in murine MLL cells overlapped significantly with those that occurred following deletion of wild-type MLL1, which is required for MLL1 fusion–driven leukemia, and indicated a shift toward a more differentiated state. Furthermore, MM-401 treatment selectively inhibited the growth of murine MLL fusion–expressing leukemia cells but not normal bone marrow cells via cell-cycle arrest, apoptosis, and enhanced myeloid differentiation. Importantly, antiproliferative effects of MM-401 were also observed in human leukemia cell lines harboring a single-allele MLL1 translocation and in patient-derived leukemia blasts with MLL1 rearrangements. Together, these results suggest that MLL1 methyltransferase activity regulates transcriptional programming in MLL and highlight how the MLL1–WDR5 interaction can be exploited to study MLL1-specific functions and to develop potential therapeutics for MLL1-associated leukemia.