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Human chromosome 11q23 translocations disrupting  MLL  result in poor prognostic leukemias. It fuses the common MLL N-terminal ∼1400 amino acids in-frame with &gt;60 different partners without shared characteristics. In addition to the well-characterized activity of MLL in maintaining  Hox  gene expression, our recent studies established an MLL–E2F axis in orchestrating core cell cycle gene expression including  Cyclin s. Here, we demonstrate a biphasic expression of MLL conferred by defined windows of degradation mediated by specialized cell cycle E3 ligases. Specifically, SCF Skp2  and APC Cdc20  mark MLL for degradation at S phase and late M phase, respectively. Abolished peak expression of MLL incurs corresponding defects in G1/S transition and M-phase progression. Conversely, overexpression of MLL blocks S-phase progression. Remarkably, MLL degradation initiates at its N-terminal ∼1400 amino acids, and tested prevalent MLL fusions are resistant to degradation. Thus, impaired degradation of MLL fusions likely constitutes the universal mechanism underlying all MLL leukemias. Our data conclude an essential post-translational regulation of MLL by the cell cycle ubiquitin/proteasome system (UPS) assures the temporal necessity of MLL in coordinating cell cycle progression.

genes and development

Bimodal degradation of MLL by SCF<sup>Skp2</sup> and APC<sup>Cdc20</sup> assures cell cycle execution: a critical regulatory circuit lost in leukemogenic MLL fusions

Bimodal degradation of MLL by SCFSkp2 and APCCdc20 assures cell cycle execution: a critical regulatory circuit lost in leukemogenic MLL fusions

Bimodal degradation of MLL by SCF^Skp2 and APC^Cdc20 assures cell cycle execution: a critical regulatory circuit lost in leukemogenic MLL fusions