Taken together, our data demonstrated that the fusion oncoprotein PML-RARα acts through extensive chromatin binding and looping genome-wide and results in strong ectopic chromatin interactions that extend across the boundaries of CTCF-defined chromatin architectures in normal myeloid cells, thus leading to the topological reorganization of the myeloid genome into aberrant configurations in APL cells. Here, PML is linked to acute promyelocytic leukemia.