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- Parker, H., et al.
(författare)
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Genomic disruption of the histone methyltransferase SETD2 in chronic lymphocytic leukaemia
- 2016
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Ingår i: Leukemia. - : Springer Science and Business Media LLC. - 0887-6924 .- 1476-5551. ; 30:11, s. 2179-2186
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Tidskriftsartikel (refereegranskat)abstract
- Histone methyltransferases (HMTs) are important epigenetic regulators of gene transcription and are disrupted at the genomic level in a spectrum of human tumours including haematological malignancies. Using high-resolution single nucleotide polymorphism (SNP) arrays, we identified recurrent deletions of the SETD2 locus in 3% (8/261) of chronic lymphocytic leukaemia (CLL) patients. Further validation in two independent cohorts showed that SETD2 deletions were associated with loss of TP53, genomic complexity and chromothripsis. With next-generation sequencing we detected mutations of SETD2 in an additional 3.8% of patients (23/602). In most cases, SETD2 deletions or mutations were often observed as a clonal event and always as a mono-allelic lesion, leading to reduced mRNA expression in SETD2-disrupted cases. Patients with SETD2 abnormalities and wild-type TP53 and ATM from five clinical trials employing chemotherapy or chemo-immunotherapy had reduced progression-free and overall survival compared with cases wild type for all three genes. Consistent with its postulated role as a tumour suppressor, our data highlight SETD2 aberration as a recurrent, early loss-of-function event in CLL pathobiology linked to aggressive disease.
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| 5. |
- 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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| 7. |
- Gerousi, M, et al.
(författare)
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The Calcitriol/Vitamin D Receptor System Regulates Key Immune Signaling Pathways in Chronic Lymphocytic Leukemia
- 2021
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Ingår i: Cancers. - : MDPI AG. - 2072-6694. ; 13:2
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Tidskriftsartikel (refereegranskat)abstract
- It has been proposed that vitamin D may play a role in prevention and treatment of cancer while epidemiological studies have linked vitamin D insufficiency to adverse disease outcomes in various B cell malignancies, including chronic lymphocytic leukemia (CLL). In this study, we sought to obtain deeper biological insight into the role of vitamin D and its receptor (VDR) in the pathophysiology of CLL. To this end, we performed expression analysis of the vitamin D pathway molecules; complemented by RNA-Sequencing analysis in primary CLL cells that were treated in vitro with calcitriol, the biologically active form of vitamin D. In addition, we examined calcitriol effects ex vivo in CLL cells cultured in the presence of microenvironmental signals, namely anti-IgM/CD40L, or co-cultured with the supportive HS-5 cells; and, CLL cells from patients under ibrutinib treatment. Our study reports that the calcitriol/VDR system is functional in CLL regulating signaling pathways critical for cell survival and proliferation, including the TLR and PI3K/AKT pathways. Moreover, calcitriol action is likely independent of the microenvironmental signals in CLL, since it was not significantly affected when combined with anti-IgM/CD40L or in the context of the co-culture system. This finding was also supported by our finding of preserved calcitriol signaling capacity in CLL patients under ibrutinib treatment. Overall, our results indicate a relevant biological role for vitamin D in CLL pathophysiology and allude to the potential clinical utility of vitamin D supplementation in patients with CLL.
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| 11. |
- Ntoufa, S, et al.
(författare)
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RPS15 mutations rewire RNA translation in chronic lymphocytic leukemia
- 2021
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Ingår i: Blood advances. - : American Society of Hematology. - 2473-9537 .- 2473-9529. ; 5:13, s. 2788-2792
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Tidskriftsartikel (refereegranskat)abstract
- Recent studies of chronic lymphocytic leukemia (CLL) have reported recurrent mutations in the RPS15 gene, which encodes the ribosomal protein S15 (RPS15), a component of the 40S ribosomal subunit. Despite some evidence about the role of mutant RPS15 (mostly obtained from the analysis of cell lines), the precise impact of RPS15 mutations on the translational program in primary CLL cells remains largely unexplored. Here, using RNA sequencing and ribosome profiling, a technique that involves measuring translational efficiency, we sought to obtain global insight into changes in translation induced by RPS15 mutations in CLL cells. To this end, we evaluated primary CLL cells from patients with wild-type or mutant RPS15 as well as MEC1 CLL cells transfected with mutant or wild-type RPS15. Our data indicate that RPS15 mutations rewire the translation program of primary CLL cells by reducing their translational efficiency, an effect not seen in MEC1 cells. In detail, RPS15 mutant primary CLL cells displayed altered translation efficiency of other ribosomal proteins and regulatory elements that affect key cell processes, such as the translational machinery and immune signaling, as well as genes known to be implicated in CLL, hence highlighting a relevant role for RPS15 in the natural history of CLL.
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