Suzuki Kohjin, Watanabe Naoki, Torii Satoru, Arakawa Satoko, Ochi Kiyosumi, Tsuchiya Shun, Yamada Kazuhiro, Kawamura Yoko, Ota Sadao, Komatsu Norio, Shimizu Shigeomi, Ando Miki, Takaku Tomoiku
Department of Hematology, Juntendo University Graduate School of Medicine, Tokyo, Japan.
System Technologies Laboratory, Sysmex Corporation, Kobe, Japan.
Cancer Sci. 2025 Mar;116(3):673-689. doi: 10.1111/cas.16424. Epub 2024 Dec 9.
The BCR::ABL1 oncogene plays a crucial role in the development of chronic myeloid leukemia (CML). Previous studies have investigated the involvement of mitochondrial dynamics in various cancers, revealing potential therapeutic strategies. However, the impact of BCR::ABL1 on mitochondrial dynamics remains unclear. In this study, we demonstrated that BCR::ABL1 is sufficient to induce excessive mitochondrial fragmentation by activating dynamin-related protein (DRP)1 through the mitogen-activated protein kinase (MAPK) pathway. Leukocytes obtained from patients with CML and the BCR::ABL1-positive cell lines exhibited increased mitochondrial fragmentation compared to leukocytes obtained from healthy donors and BCR::ABL1-negative cells. Furthermore, the analysis of BCR::ABL1-transduced cells showed increased phosphorylation of DRP1 at serine 616 and extracellular signal-regulated kinase (ERK) 1/2. Moreover, the inhibition of DRP1 and upstream mitogen-activated extracellular signal-regulated kinase (MEK) 1/2 suppressed mitochondrial fragmentation. Strikingly, DRP1 inhibition effectively reduced the viability of BCR::ABL1-positive cells and induced necrotic cell death. Additionally, a label-free artificial intelligence-driven flow cytometry successfully identified not only the BCR::ABL1-transduced cells but also peripheral leukocytes from CML patients by assessing mitochondrial morphological alterations. These findings suggested the crucial role of BCR::ABL1-induced mitochondrial fragmentation in driving BCR::ABL1-positive cell proliferation, and the potential use of mitochondrial morphological alterations as a clinical biomarker for the label-free detection of CML cells.
:ABL1致癌基因在慢性髓性白血病（CML）的发展中起着关键作用。先前的研究调查了线粒体动力学在各种癌症中的参与情况，揭示了潜在的治疗策略。然而，BCR::ABL1对线粒体动力学的影响仍不清楚。在本研究中，我们证明BCR::ABL1足以通过丝裂原活化蛋白激酶（MAPK）途径激活动力蛋白相关蛋白（DRP）1来诱导过度的线粒体碎片化。与从健康供体获得的白细胞和BCR::ABL1阴性细胞相比，从CML患者获得的白细胞和BCR::ABL1阳性细胞系表现出线粒体碎片化增加。此外，对BCR::ABL1转导细胞的分析显示，DRP1在丝氨酸616和细胞外信号调节激酶（ERK）1/2处的磷酸化增加。此外，抑制DRP1和上游丝裂原活化细胞外信号调节激酶（MEK）1/2可抑制线粒体碎片化。令人惊讶的是，DRP1抑制有效地降低了BCR::ABL1阳性细胞的活力并诱导坏死性细胞死亡。此外，一种无标记的人工智能驱动的流式细胞术不仅成功地识别了BCR::ABL1转导的细胞，还通过评估线粒体形态改变识别了CML患者的外周白细胞。这些发现表明BCR::ABL1诱导的线粒体碎片化在驱动BCR::ABL1阳性细胞增殖中起关键作用，以及线粒体形态改变作为无标记检测CML细胞的临床生物标志物的潜在用途。
