As the results obtained in S100A3-silenced HL-60 and NB4 cells exposed to ATRA are substantially similar, our data indicate that the cellular context rather than PML-RARα expression is the major determinant of the different effects exerted by S100A3 on RARα functional activity in myeloid leukemia relative to breast cancer and lung cancer cells. Here, PML is linked to myeloid leukemia.