PML/RARα fusion Gene and Response to Retinoic Acid and Arsenic Trioxide Treatment

The leukaemia-associated fusion gene, promyelocytic leukaemia (PML)-retinoic acid receptor-\u3b1 (RAR\u3b1), causes acute promyelocytic leukaemia (APL) by blocking differentiation and increasing self-renewal of leukaemic progenitor cells. The current standard of APL\u2019s induction therapy comprises all-trans retinoic acid (ATRA) and chemotherapy, but arsenic trioxide also cures many patients and is used routinely in the treatment of relapsed patients. When combined with ATRA and chemotherapy, a 5-year overall survival of 90% is achieved. Molecularly, ATRA at pharmacological doses unblocks the transcriptional repression brought upon by the PML/RAR\u3b1 chimeric protein. Arsenic, on the other hand, binds thiol residues and inducesthe formation of reactive oxygen species, consequently affecting numerous signalling pathways. Both agents target the fusion protein for degradation, albeit via diverse mechanisms. Moreover, ATRA synergises with arsenic in eliminating leukaemia-initiating cells (LICs) also referred to as leukaemic stem cells (LSC). The progress made in the treatment of patients with APL constitutes an example of a success story of translational haematology towards which both basic scientists and clinicians have contributed over the years