CBX8, a Polycomb Group Protein, Is Essential for MLL-AF9-Induced Leukemogenesis

Chromosomal translocations involving the mixed lineage leukemia ( MLL) gene lead to the development of acute leukemias. Constitutive HOX gene activation by MLL fusion proteins is required for MLL-mediated leukemogenesis; however, the underlying mechanisms remain elusive. Here, we show that chromobox homolog 8 (CBX8), a Polycomb Group protein that interacts with MLL-AF9 and TIP60, is required for MLL-AF9-induced transcriptional activation and leukemogenesis. Conversely, both CBX8 ablation and specific disruption of the CBX8 interaction by point mutations in MLL-AF9 abrogate HOX gene upregulation and abolish MLL-AF9 leukemic transformation. Surprisingly, Cbx8-deficient mice are viable and display no apparent hematopoietic defects. Together, our findings demonstrate that CBX8 plays an essential role in MLL-AF9 transcriptional regulation and leukemogenesis. ► CBX8 is essential for both initiation and maintenance of MLL-AF9 transformation ► CBX8 is crucial for MLL-AF9-induced transcriptional activation ► Role of CBX8 in MLL-AF9 leukemogenesis is independent of PRC1 ► CBX8 regulation of TIP60 localization contributes to MLL-AF9 transformation