Model for the regulation of MLL degradation and HOX gene expression by ASB2 during normal and malignant hematopoiesis. (A) In hematopoietic stem cell and progenitor compartments, MLL maintains HOX gene expression. (B) During differentiation, ASB2 expression is induced, which leads to MLL ubiquitination and degradation. Less MLL is localized to HOX gene loci, resulting in inhibition of HOX gene transcription. (C) In MLL fusion protein-mediated leukemia, MLL fusion proteins lack the PHD/Bromo region that interacts with ASB2 and escape from ASB2-mediated degradation. Moreover, low expression of ASB2 leads to stabilization of wild-type MLL, which may also contribute to the constitutive activation of HOX genes and leukemogenesis.