Figure 2.

Targeting ATRA-resistant APL. In most of the cases, ATRA treatment induces degradation of RARalpha fusion and APL cell differentiation, resulting in complete remission. However, some APL patients are refractory to ATRA, or in some cases ATRA treatment may select/evolve drug-resistant clones that are no longer responsive to ATRA. Several approaches have been proposed to target ATRA-resistant APL. These include (1) retinoid derivatives with a higher affinity to the fusions; (2) ATO that binds to the PML moiety of the fusion and subsequently induces degradation of the onco-fusion; (3) HDACi that facilitate histone acetylation; and (4) overexpression or hyperphosphorylation of PHF8 that removes the repressive H3K9me2 mark to turn on the differentiation transcriptional programme.