Arterial thrombosis: going, gone!

phagic vesicles after treatment with these agents. Functionally, activation of autophagy by the mammalian target of rapamycin (mTOR) inhibitor triggers PML/RARA destabilization in the NB4 APL cell line, resulting in enhanced ATRA-induced differentiation. Conversely, the autophagy inhibitor BafA impedes treatment-induced PML/ RARA degradation and biologic response. These results are important in several respects. They identify a novel cytoplasmic PML/RARA catabolic pathway and explain why some studies had observed PML/RARA in the cytoplasm. Other oncogenic fusion proteins may share similar features of poor solubility and may be targets of autophagy. This study also raises interesting questions as to the possible links between autophagy and PML, which is highly stress-sensitive and may also assemble into cytoplasmic bodies.4 Finally, PML suppresses mTOR activity,10 a key inhibitor of the autophagic process. Then, release of PML from PML/RARA by ATRA or As2O3 treatment induces a self-perpetuating cycle accelerating PML/RARA degradation. The latter could be implicated in enhanced differentiation, as suggested in the Isakson study, but also in loss of self-renewal of APL clonogenic progenitors. Thus, modulation of autophagy in APL could have important therapeutic consequences. Conflict-of-interest disclosure: The authors declare no competing financial interests. ■