Working model. (A) The effect of wild-type MLL on the stability of RUNX1/CBFβ results in HSC differentiation. In the state of wild-type MLL, the downregulation of RUNX1/CBFβ mediated by the CXXC domain is intrinsically inhibited by PHD finger domains. High levels of RUNX1 will induce HSC differentiation. (B) MLL oncoproteins lose the ability to inhibit the CXXC domain via the PHD finger domains and the RUNX1/CBFβ protein complex is constitutively downregulated. X, the possible protein or complex that mediates the effect of CXXC domain and flanking region to RUNX1/CBFβ. (Upper panel) In MLL fusion proteins, the PHD finger domains can no longer inhibit the CXXC domain. (Lower panel) MLL-PTD has only a single PHD finger domain, yet still contains 2 CXXC domains, leaving 1 CXXC domain free to downregulate RUNX1/CBFβ constitutively and promote HSC self-renewal. Subsequent mutations then cooperate to lead to AML development.