Novel insights into the ULK2-FIP200-AMPK-mediated regulation of autophagy and BCR::ABL degradation in chronic myeloid leukemia.

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm driven by the BCR::ABL fusion tyrosine kinase. AMP-activated protein kinase (AMPK) plays a pivotal role in regulating cellular energy homeostasis, ensuring an adequate ATP supply for CML cell proliferation. ULK1, a well-known AMPK substrate, is a critical serine/threonine kinase in the autophagy initiation complex. ULK2, a paralog of ULK1, shares approximately 50 % amino acid sequence homology and has been reported to function complementarily with ULK1. However, emerging evidence suggests that ULK2 also has unique functions distinct from those of ULK1. Public RNA sequencing data revealed that ULK2 expression is significantly lower in hematopoietic cells compared to other tissues. To explore the function of ULK2, we performed in vitro assays using 293FT cells, which endogenously express high levels of ULK2. Mass spectrometry analysis demonstrated that ULK2 forms a stable complex with FIP200, which in turn interacts specifically with the AMPK α1 and γ1 subunits. Furthermore, shRNA-mediated knockdown of ULK2 induced AMPK activation and promoted the cytoplasmic accumulation of ULK1 and FIP200, thereby inducing autophagy in CML cells. Although autophagy typically acts as a cytoprotective mechanism, in this context, the autophagy-dependent degradation of BCR::ABL induced cell death. These findings reveal a novel regulatory axis involving ULK2, FIP200, AMPK, and autophagy, suggesting a unique role for ULK2 in CML pathophysiology and offering potential therapeutic insights.