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Haematologica 2021 Volume 106(3):692-700
Chronic Lymphocytic Leukemia
Stem cell factor is implicated in microenvironmental interactions and cellular dynamics of chronic lymphocytic leukemia
George I. Gavriilidis,1* Stavroula Ntoufa,2* Nikos Papakostantinou,2 Konstantia Kotta,2 Triantafyllia Koletsa,3 Elisavet Chartomatsidou,2 Theodoros Moysiadis,2,4 Niki Stavroyianni,5 Achilles Anagnostopoulos,5 Eleni Papadaki,6 Asterios S. Tsiftsoglou1 and Kostas Stamatopoulos2,4
1Laboratory of Pharmacology, School of Pharmacy, Aristotle University of Thessaloniki, Thessaloniki, Greece; 2Institute of Applied Biosciences, Centre for Research and Technology Hellas, Thessaloniki, Greece; 3Department of Pathology, Faculty of Medicine, Aristotle University, Thessaloniki, Greece; 4Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden; 5Hematology Department and HCT Unit, G. Papanicolaou Hospital, Thessaloniki, Greece and 6Department of Medicine, University of Crete, Heraklion, Greece
*GIG and SN contributed equally as co-first authors.
ABSTRACT
The inflammatory cytokine stem cell factor (SCF, ligand of c-kit recep- tor) 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 lympho- cytic leukemia (CLL), however its precise role in CLL pathophysiology remains elusive. In this study, CLL cells were found to express predomi- nantly 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 pri- marily 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.
Introduction
Chronic inflammation facilitates the survival, proliferation and immune evasion of chronic lymphocytic leukemia (CLL) cells in their tissue microenvironments.1,2 CLL cells aberrantly express pro-inflammatory mediators such as cytokines and chemokines due to intrinsic abnormalities (e.g., mutations in MYD88, NOTCH1 or other genes) or extrinsic determinants (e.g., antigenic stimulation of B-cell receptors [BcR] and Toll-like receptors [TLR]).1,3 Moreover, CLL cells further exacerbate the inflammatory character of their respective tumor milieu by modulating their sur- rounding cells in a pro-oncogenic fashion.4
Inflammation in the CLL milieu is linked with the clinical heterogeneity of the disease since increased levels of cytokines/chemokines correlate with adverse prog- nostic markers such as high ZAP70 and CD38 expression, unmutated IGHV genes, aggressive stereotyped subsets (e.g., subset #1) and adverse prognostic chromoso- mal aberrations such as del(11q) and del(17p).5–7 Gradually, inflammation favors the expansion of more aggressive CLL clones that ultimately lead to chemorefractori-
Correspondence:
KOSTAS STAMATOPOULOS
kostas.stamatopoulos@certh.gr
Received: August 29, 2019. Accepted: March 24, 2020. Pre-published: March 26, 2020.
https://doi.org/10.3324/haematol.2019.236513
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