Hematology and Clinical Immunology Unit, Department of Medicine, University of Padova, Padua, Italy.
Br J Haematol. 2023 Oct;203(2):224-236. doi: 10.1111/bjh.18996. Epub 2023 Jul 26.
Signalling events downstream the B-cell receptor (BCR) are central for the survival and progression of chronic lymphocytic leukaemia (CLL) cells. Focal adhesion kinase (FAK), regulated through calpain, interacts with molecules of BCR signalling, cytoskeletal modelling and disease progression, such as Src/Lyn, cortactin and HS1. Hypothesizing that FAK might play a key role in CLL pathogenesis, we observed a down-modulation of FAK whole form, associated with FAK cleavage due to calpain activity upon BCR stimulation. Patients, whose cells were able to release Ca after BCR stimulation, had less amount of full-length FAK, which translated into a higher presence of cleaved/activated form of the protein phosphorylated at Y397, these features being mostly shown by immunoglobulin heavy chain (IGHV)-unmutated poor-prognosis patients. Moreover, we found that cortactin and HS1 proteins were overexpressed in those cells, suggesting a possible interplay with FAK. Treatment with the FAK inhibitor Defactinib was able to induce apoptosis in CLL cells. In conclusion, the malignant phenotype in unfavourable-prognosis patients seems to be encouraged by the overexpression of cortactin and HS1, that, together with FAK, may be involved in a druggable pathogenetic pathway in CLL.
BCR 下游的信号事件是慢性淋巴细胞白血病（CLL）细胞存活和进展的核心。钙蛋白酶调节的粘着斑激酶（FAK）与 BCR 信号、细胞骨架建模和疾病进展的分子相互作用，如 Src/Lyn、cortactin 和 HS1。假设 FAK 可能在 CLL 发病机制中发挥关键作用，我们观察到 FAK 全形式的下调，这与 BCR 刺激时钙蛋白酶活性引起的 FAK 裂解有关。在 BCR 刺激后能够释放 Ca 的患者，其全长 FAK 数量较少，这转化为 Y397 磷酸化的裂解/激活形式的蛋白的存在更高，这些特征主要由 IGHV-未突变的预后不良患者表现出来。此外，我们发现 cortactin 和 HS1 蛋白在这些细胞中过度表达，表明它们可能与 FAK 相互作用。用 FAK 抑制剂 Defactinib 治疗能够诱导 CLL 细胞凋亡。总之，不良预后患者的恶性表型似乎受到 cortactin 和 HS1 的过度表达的促进，FAK 可能与它们一起参与 CLL 中可用药理的致病途径。
