Absence of natural intracellular retinoids in mouse bone marrow cells and implications for PML-RARA transformation.

The X-RARA fusion proteins have reduced sensitivity to all-trans-retinoic acid (ATRA), and have been proposed to act by decreasing retinoid-dependent transcription required for myeloid maturation.1, 2, 3 We therefore sought to determine whether maturing myeloid cells are exposed to natural retinoid ligands in vivo. Surprisingly, we detected a paucity of natural retinoids capable of transactivating RARA-dependent transcription in adult mouse bone marrow cells, and the trace activity we observed tended to be in erythroid-lineage cells, rather than in myeloid-progenitors. This suggests that the resistance to retinoid-mediated transactivation likely has a limited role in X-RARA-dependent leukemogenesis because natural retinoids are largely absent during normal myeloid maturation.