Sampietro Marta, Cassina Valeria, Salerno Domenico, Barbaglio Federica, Buglione Enrico, Marrano Claudia Adriana, Campanile Riccardo, Scarfò Lydia, Biedenweg Doreen, Fregin Bob, Zamai Moreno, Díaz Torres Alfonsa, Labrador Cantarero Veronica, Ghia Paolo, Otto Oliver, Mantegazza Francesco, Caiolfa Valeria R, Scielzo Cristina
School of Medicine and Surgery, BioNanoMedicine Center NANOMIB, Università di Milano-Bicocca, Vedano al Lambro, Italy.
Unit of Malignant B cells biology and 3D modelling, Division of Experimental Oncology, IRCCS Ospedale San Raffaele, Milan, Italy.
Hemasphere. 2023 Jul 21;7(8):e931. doi: 10.1097/HS9.0000000000000931. eCollection 2023 Aug.
Chronic lymphocytic leukemia (CLL) is an incurable disease characterized by an intense trafficking of the leukemic cells between the peripheral blood and lymphoid tissues. It is known that the ability of lymphocytes to recirculate strongly depends on their capability to rapidly rearrange their cytoskeleton and adapt to external cues; however, little is known about the differences occurring between CLL and healthy B cells during these processes. To investigate this point, we applied a single-cell optical (super resolution microscopy) and nanomechanical approaches (atomic force microscopy, real-time deformability cytometry) to both CLL and healthy B lymphocytes and compared their behavior. We demonstrated that CLL cells have a specific actomyosin complex organization and altered mechanical properties in comparison to their healthy counterpart. To evaluate the clinical relevance of our findings, we treated the cells in vitro with the Bruton's tyrosine kinase inhibitors and we found for the first time that the drug restores the CLL cells mechanical properties to a healthy phenotype and activates the actomyosin complex. We further validated these results in vivo on CLL cells isolated from patients undergoing ibrutinib treatment. Our results suggest that CLL cells' mechanical properties are linked to their actin cytoskeleton organization and might be involved in novel mechanisms of drug resistance, thus becoming a new potential therapeutic target aiming at the normalization of the mechanical fingerprints of the leukemic cells.
慢性淋巴细胞白血病（CLL）是一种无法治愈的疾病，其特征是白血病细胞在外周血和淋巴组织之间频繁迁移。已知淋巴细胞的再循环能力在很大程度上取决于它们快速重新排列细胞骨架并适应外部信号的能力；然而，对于在这些过程中CLL细胞与健康B细胞之间出现的差异，我们知之甚少。为了研究这一点，我们对CLL细胞和健康B淋巴细胞都应用了单细胞光学（超分辨率显微镜）和纳米力学方法（原子力显微镜、实时变形性细胞术），并比较了它们的行为。我们证明，与健康细胞相比，CLL细胞具有特定的肌动球蛋白复合物组织，并且其力学性质发生了改变。为了评估我们研究结果的临床相关性，我们在体外用布鲁顿酪氨酸激酶抑制剂处理细胞，首次发现该药物可将CLL细胞的力学性质恢复到健康表型，并激活肌动球蛋白复合物。我们进一步在接受依鲁替尼治疗的患者分离出的CLL细胞上进行了体内验证。我们的结果表明，CLL细胞的力学性质与其肌动蛋白细胞骨架组织有关，可能参与了新的耐药机制，从而成为旨在使白血病细胞力学指纹正常化的新潜在治疗靶点。
