Cytosolic DNA sensing combined with differentiation therapy induces irreversible differentiation and cell growth arrest in myeloid leukemia cells

Abstract Accumulating evidence indicates that various oncogenic mutations interfere with normal myeloid differentiation of leukemogenic cells during the early process of acute myeloid leukemia (AML) development. Differentiation therapy is an ideal therapeutic strategy capable of terminating leukemic expansion by reactivating the differentiation potential; however, the plasticity and instability of leukemia cells counteract the establishment of curative treatment for AML. Thus, the viable strategy for irreversible differentiation is urgently required. Based on our previous observation that autophagy inhibitor treatment induces the accumulation of cytosolic DNA and activation of cytosolic DNA-sensor signaling selectively in leukemia cells, we herein examined the synergistic effect of cytosolic DNA-sensor signaling activation with conventional differentiation therapy on AML. The combined treatment succeeded in inducing irreversible differentiation in AML cells. Mechanistically, cytosolic DNA was sensed by absent in melanoma 2 (AIM2), a cytosolic DNA sensor. Activation of the AIM2 inflammasome resulted in the accumulation of p21 through the inhibition of its proteasomal degradation, thereby facilitatingthe myeloid differentiation. Importantly, the combined therapy dramatically reduced the total leukemia cell counts and proportion of blast cells in the spleens of AML mice. Collectively, these findings indicate that the activation of cytosolic DNA-sensor signaling in combination with conventional differentiation therapy can be an effective approach to drive the irreversible differentiation of leukemia cells.