Acute promyelocytic Leukemia (APL) is driven by the PML/RARA fusion protein. PML/RARA, is a potent transcriptional repressor and also disrupts PML bodies, both initiating the differentiation block and self-renewal of leukemic cells. Two therapeutic agents, retinoic acid and arsenic trioxide, induce differentiation of leukemic promyelocytes and clinical remission of APL patients. Using genetic and pharmacological evidence, we have recently demonstrated that RA-induced differentiation and leukemia initiating cell (LIC) clearance may be uncoupled.
Retinoic acid (RA) and arsenic trioxide both trigger PML/RARA degradation by the proteasome. Remarkably, these two therapeutic agents each directly target the two constitutive moieties of PML/RARA: arsenic binding PML and RA binding RARA. The RA/arsenic trioxide combination dramatically synergizes for PML/RARA degradation, and definitively cures APL mice and in the immense majority of patients. We have recently shown that PML/RARA degradation allows the reformation of PML nuclear bodies and the activation of P53. In mice PML and P53 are both required for therapy-induced APL clearance. Mutations in PML and P53 have been described in very rare therapy-resistant patients. This PML/P53 axis does not drive apoptosis, but a senescence-like program. Circumstantial evidence links this axis to loss of leukemia-initiating activity in other cancers. Thus, APL represents the first clinical example of oncogene-targeted cure for cancer.