Koyama Daisuke, Yamamoto Naoki, Abe Takaaki, Suzuki Kengo, Sato Yuki, Suzuki Manabu, Shibayama Naoya, Ikezoe Takayuki
Department of Hematology, Fukushima Medical University, 1 Hikarigaoka, Fukushima, 960-1295, Japan.
Divison of Biophysics, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi, 329-0498, Japan.
Biochem Biophys Res Commun. 2025 Jul 13;778:152343. doi: 10.1016/j.bbrc.2025.152343.
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.
慢性粒细胞白血病（CML）是一种由BCR::ABL融合酪氨酸激酶驱动的骨髓增殖性肿瘤。AMP激活的蛋白激酶（AMPK）在调节细胞能量稳态中起关键作用，确保为CML细胞增殖提供充足的ATP供应。ULK1是一种著名的AMPK底物，是自噬起始复合物中的关键丝氨酸/苏氨酸激酶。ULK2是ULK1的旁系同源物，氨基酸序列同源性约为50%，据报道其与ULK1具有互补功能。然而，新出现的证据表明，ULK2也具有与ULK1不同的独特功能。公共RNA测序数据显示，与其他组织相比，造血细胞中ULK2的表达显著降低。为了探究ULK2的功能，我们使用内源性高水平表达ULK2的293FT细胞进行了体外实验。质谱分析表明，ULK2与FIP200形成稳定复合物，而FIP200又与AMPK α1和γ1亚基特异性相互作用。此外，shRNA介导的ULK2敲低诱导了AMPK激活，并促进了ULK1和FIP200的细胞质积累，从而诱导CML细胞发生自噬。尽管自噬通常作为一种细胞保护机制，但在此情况下，BCR::ABL的自噬依赖性降解诱导了细胞死亡。这些发现揭示了一个涉及ULK2、FIP200、AMPK和自噬的新调控轴，表明ULK2在CML病理生理学中具有独特作用，并提供了潜在的治疗见解。
