Autophagy regulates myeloid cell differentiation by p62/SQSTM1-mediated degradation of PML-RARα oncoprotein

PML-RAR alpha oncoprotein is a fusion protein of promyelocytic leukemia (PML) and the retinoic acid receptor-alpha (RAR alpha) and causes acute promyelocytic leukemias (APL). A hallmark of all-trans retinoic acid (ATRA) responses in APL is PML-RAR alpha degradation, which promotes cell differentiation. Here, we demonstrated that autophagy is a crucial regulator of PML-RAR alpha degradation. Inhibition of autophagy by short hairpin (sh) RNA that target essential autophagy genes such as ATG1, ATG5 and PI3KC3, and by autophagy inhibitors (e. g., 3-methyladenine), blocked PML-RAR alpha degradation and subsequently granulocytic differentiation of human myeloid leukemic cells. In contrast, rapamycin, the mTOR kinase inhibitor, enhanced autophagy and promoted ATRA-induced PML-RAR alpha degradation and myeloid cell differentiation. Moreover, PML-RAR alpha co-immunoprecipitated with the ubiquitin-binding adaptor protein p62/SQSTM1, which is degraded through autophagy. Furthermore, knockdown of p62/SQSTM1 inhibited ATRA-induced PML-RAR alpha degradation and myeloid cell differentiation. The identification of PML-RAR alpha as a target of autophagy provides new insight into the mechanism of action of ATRA and its specificity for APL.