Laboratory of Pharmacology, School of Pharmacy, Aristotle University of Thessaloniki, Thessaloniki, Greece
Institute of Applied Biosciences, Centre for Research and Technology Hellas, Thessaloniki, Greece
Haematologica. 2021 Mar 1;106(3):692-700. doi: 10.3324/haematol.2019.236513.
The inflammatory cytokine stem cell factor (SCF, ligand of c-kit receptor) has been implicated as a pro-oncogenic driver and an adverse prognosticator in several human cancers. Increased SCF levels have recently been reported in a small series of patients with chronic lymphocytic leukemia (CLL), however its precise role in CLL pathophysiology remains elusive. In this study, CLL cells were found to express predominantly the membrane isoform of SCF, which is known to elicit a more robust activation of the c-kit receptor. SCF was significantly overexpressed in CLL cells compared to healthy tonsillar B cells and it correlated with adverse prognostic biomarkers, shorter time-to-first treatment and shorter overall survival. Activation of immune receptors and long-term cell-cell interactions with the mesenchymal stroma led to an elevation of SCF primarily in CLL cases with an adverse prognosis. Contrariwise, suppression of oxidative stress and the BTK inhibitor ibrutinib lowered SCF levels. Interestingly, SCF significantly correlated with mitochondrial dynamics and hypoxia-inducible factor-1a which have previously been linked with clinical aggressiveness in CLL. SCF was able to elicit direct biological effects in CLL cells, affecting redox homeostasis and cell proliferation. Overall, the aberrantly expressed SCF in CLL cells emerges as a key response regulator to microenvironmental stimuli while correlating with poor prognosis. On these grounds, specific targeting of this inflammatory molecule could serve as a novel therapeutic approach in CLL.
炎症细胞因子干细胞因子 (SCF，c-kit 受体的配体) 已被认为是多种人类癌症中的致癌驱动因子和不良预后标志物。最近在一小部分慢性淋巴细胞白血病 (CLL) 患者中报道了 SCF 水平升高，但其在 CLL 病理生理学中的确切作用仍不清楚。在这项研究中，发现 CLL 细胞主要表达 SCF 的膜型，这已知会引发更强烈的 c-kit 受体激活。与健康扁桃体 B 细胞相比，CLL 细胞中 SCF 的表达明显上调，并且与不良预后生物标志物、首次治疗时间更短和总生存期更短相关。免疫受体的激活和与间充质基质的长期细胞间相互作用导致 SCF 主要在预后不良的 CLL 病例中升高。相反，抑制氧化应激和 BTK 抑制剂伊布替尼可降低 SCF 水平。有趣的是，SCF 与先前与 CLL 临床侵袭性相关的线粒体动力学和缺氧诱导因子-1a 显著相关。SCF 能够在 CLL 细胞中引发直接的生物学效应，影响氧化还原稳态和细胞增殖。总的来说，CLL 细胞中异常表达的 SCF 作为对微环境刺激的关键反应调节剂，与不良预后相关。基于这些原因，针对这种炎症分子的特异性靶向可能成为 CLL 的一种新的治疗方法。
