Abstract
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.