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- Gavriilidis, GI, et al.
(författare)
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Stem cell factor is implicated in microenvironmental interactions and cellular dynamics of chronic lymphocytic leukemia
- 2021
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Ingår i: Haematologica. - : Ferrata Storti Foundation (Haematologica). - 1592-8721 .- 0390-6078. ; 106:3, s. 692-700
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Tidskriftsartikel (refereegranskat)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 predominantly express the membrane isoform of SCF that 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 whilst 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 adverse-prognostic CLL cases. On the contrary, suppression of oxidative stress and the BTK inhibitor Ibrutinib negated SCF levels. Interestingly, SCF significantly correlated with mitochondrial dynamics and HIF-1α 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 whilst correlating with poor prognosis. On these grounds, specific targeting of this inflammatory molecule could serve as a novel therapeutic approach in CLL.
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| 4. |
- Zaragoza-Infante, L, et al.
(författare)
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IgIDivA: immunoglobulin intraclonal diversification analysis
- 2022
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Ingår i: Briefings in bioinformatics. - : Oxford University Press (OUP). - 1477-4054 .- 1467-5463. ; 23:5
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Tidskriftsartikel (refereegranskat)abstract
- Intraclonal diversification (ID) within the immunoglobulin (IG) genes expressed by B cell clones arises due to ongoing somatic hypermutation (SHM) in a context of continuous interactions with antigen(s). Defining the nature and order of appearance of SHMs in the IG genes can assist in improved understanding of the ID process, shedding light into the ontogeny and evolution of B cell clones in health and disease. Such endeavor is empowered thanks to the introduction of high-throughput sequencing in the study of IG gene repertoires. However, few existing tools allow the identification, quantification and characterization of SHMs related to ID, all of which have limitations in their analysis, highlighting the need for developing a purpose-built tool for the comprehensive analysis of the ID process. In this work, we present the immunoglobulin intraclonal diversification analysis (IgIDivA) tool, a novel methodology for the in-depth qualitative and quantitative analysis of the ID process from high-throughput sequencing data. IgIDivA identifies and characterizes SHMs that occur within the variable domain of the rearranged IG genes and studies in detail the connections between identified SHMs, establishing mutational pathways. Moreover, it combines established and new graph-based metrics for the objective determination of ID level, combined with statistical analysis for the comparison of ID level features for different groups of samples. Of importance, IgIDivA also provides detailed visualizations of ID through the generation of purpose-built graph networks. Beyond the method design, IgIDivA has been also implemented as an R Shiny web application. IgIDivA is freely available at https://bio.tools/igidiva
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