Stavroula Ntoufa

The Centre for Research and Technology, Hellas · Institute of Applied Biosciences-INAB

The TA-isoform of the p63 transcription factor (TAp63) has been reported to contribute to clinical aggressiveness in chronic lymphocytic leukemia (CLL) in a hitherto elusive way. Here, we sought to further understand and define the role of TAp63 in the pathophysiology of CLL. First, we found that elevated TAp63 expression levels are linked with adv...

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 tran...

Immune deregulation has a critical role in the pathogenesis of lower risk myelodysplastic syndromes (MDS). The cells of the macrophage/monocyte lineage have been reported to contribute to the inflammatory process in MDS through impaired phagocytosis of the apoptotic hemopoietic cells and abnormal production of cytokines. In the present study we ass...

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...

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 remai...

Splenic marginal-zone lymphoma (SMZL) ontogeny and evolution is a complex process, involving, amongst others, (super)antigenic stimulation, molecular deregulation of genes involved in the physiological differentiation of splenic marginal zone B cells (e.g. NOTCH2 and KLF2), and epigenetic alterations leading to silencing of different tumor suppress...

Calcitriol, the biologically active form of vitamin D, modulates a plethora of cellular processes following its receptor ligation, namely the vitamin D receptor (VDR), a nuclear transcription factor that regulates the transcription of diverse genes. It has been proposed that vitamin D may play a role in prevention and treatment of cancer while epid...

Key Points Microenvironmental stimuli affect EZH2 expression and function in CLL. Combined B-cell signaling and EZH2 inhibition showed synergistic effects on primary CLL cells.

Background The mitogenic glycoprotein Stem Cell Factor (SCF, ligand of c‐kit receptor) has been implicated as a pro‐oncogenic driver in a variety of human cancers. Increased SCF levels have recently been reported in a small series of patients with chronic lymphocytic leukemia (CLL), however little if any evidence exists regarding its precise role i...

Background Calcitriol, the biologically active form of vitamin D, binds to the vitamin D receptor (VDR) which is translocated into the nucleus and regulates the transcription of target genes. Epidemiological studies have reported that low blood levels of vitamin D are associated with adverse disease outcome in chronic lymphocytic leukemia (CLL). Ho...

In chronic lymphocytic leukemia (CLL)the interaction of leukemic cells with the microenvironment ultimately affects patient outcome. CLL cases can be divided in two subgroups with different clinical course based on the mutational status of the immunoglobulin heavy variable (IGHV)genes: mutated CLL (M-CLL)and unmutated CLL (U-CLL). Since in CLL, the...

Recent evidence indicates that TAp63, the prevalent isoform of TP63 in Chronic Lymphocytic Leukemia (CLL), is implicated in disease pathogenesis. In CLL, TAp63 expression, modulated by both immune signaling and epigenetic modifications, promotes leukemic cell survival and homing to the bone marrow. In activated normal B cells, the TAp63 transcripti...

We and others recently reported mutations within the RPS15 gene, encoding a component of the 40S ribosomal subunit, in clinically aggressive chronic lymphocytic leukemia (CLL). RPS15 mutations resided within an evolutionary conserved region, alluding to an oncogenic rather than a tumor-suppressor role. Our pilot functional analysis revealed that, s...

Chronic lymphocytic leukemia (CLL) stereotyped subsets #6 and #8 include cases expressing unmutated B cell receptor immunoglobulin (BcR IG) (U‐CLL). Subset #6 (IGHV1‐69/IGKV3‐20) is less aggressive compared to subset #8 (IGHV4‐39/IGKV1(D)‐39) which has the highest risk for Richter's transformation among all CLL. The underlying reasons for this dive...

Cell-autonomous B-cell receptor (BcR)-mediated signalling is a hallmark feature of the neoplastic B lymphocytes in chronic lymphocytic leukaemia (CLL). Here we elucidate the structural basis of autonomous activation of CLL B cells, showing that BcR immunoglobulins initiate intracellular signalling through homotypic interactions between epitopes tha...

Supplementary figures and supplementary tables.

Supplementary Data 1 file contains the sequences of the oligonucleotide primers used for the PCR amplification of the CLL B-cell receptors cDNA, and the preparation of the CLL183 site-specific mutants.

PURPOSE: We sought to investigate if B cell receptor immunoglobulin (BcR IG) stereotypy is associated with particular clinicobiological features amongst chronic lymphocytic leukemia (CLL) patients expressing mutated BcR IG (M-CLL) encoded by the IGHV4-34 gene, and also ascertain whether these associations could refine prognostication. EXPERIMENTAL...

Toll interleukin-1 receptor 8 (also known as TIR8, SIGIRR, or IL1R8) is a transmembrane receptor that inhibits inflammation. Accordingly, genetic inactivation of this protein exacerbates chronic inflammation and inflammation-associated tumors in mice. In particular, lack of TIR8 triggers leukemia progression in a mouse model of chronic lymphocytic...

Despite the remarkable clinical results obtained with the novel kinase inhibitors i.e. the BTK inhibitor Ibrutinib and the PI3Kδ inhibitor idelalisib in both relapsed/refractory and treatment-naïve patients, most patients achieve only partial responses underscoring the existence of resistance mechanisms that warrant further investigation. Here we e...

A significant body of work on biomedical text mining is aimed at uncovering meaningful associations between biological entities, including genes. This has the potential to offer new insights for research, uncovering hidden links between genes involved in critical pathways and processes. Recently, high-throughput studies have started to unravel the...

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The nuclear factor-κB (NF-κB) pathway is constitutively activated in chronic lymphocytic leukemia (CLL) patients, and hence plays a major role in disease development and evolution. In contrast to many other mature B-cell lymphomas, only a few recurrently mutated genes involved in canonical or non-canonical NF-κB activation have been identified in C...

Malignancies of mature B cells are quite distinctive in originating from well-differentiated cells. Hence, it is not paradoxical that, similar to their normal counterparts, most mature B cell lymphoma subtypes are critically dependent on microenvironmental cues. Such external signals are sensed by various receptors present on the malignant cells, i...

In chronic lymphocytic leukemia (CLL), antigenic stimulation through the B-cell receptor (BcR) and the accumulation of genetic defects critically affect the natural history of the disease.[1][1] The importance of antigen involvement is underscored by the existence of stereotyped BcR in approximately

The histone methyltransferase EZH2 induces gene repression through trimethylation of histone H3 at lysine 27 (H3K27me3). EZH2 overexpression has been reported in many types of cancer and associated with poor prognosis. Here we investigated the expression and functionality of EZH2 in chronic lymphocytic leukemia (CLL). Aggressive cases with unmutate...

Histone methyltransferases (HMTs) are important epigenetic regulators of gene transcription and are disrupted at the genomic level in a spectrum of human tumors including haematological malignancies. Using high-resolution SNP-arrays, we identified recurrent deletions of the SETD2 locus in 3% (8/261) of chronic lymphocytic leukemia (CLL) patients. F...

Chronic lymphocytic leukemia (CLL) patients assigned to stereotyped subset #4 (mutated IGHV4-34/IGKV2-30 BCR Ig) display a particularly indolent disease course. Immunogenetic studies of the clonotypic BCR Ig of CLL subset #4 suggested a resemblance with B cells rendered anergic through chronic autoantigenic stimulation. In this article, we provide...

This chapter provides the biological background of the research regarding chronic lymphocytic leukemia (CLL) and toll-like receptor (TLR) pathways. Stimulation of TLRs induces an immediate signaling cascade resulting in the production of inflammatory cytokines and the expression of costimulatory molecules. The chapter then describes the theory and...

Key Points Whole-exome sequencing of CLL patients who relapsed after FCR treatment revealed frequent mutations in RPS15. RPS15 mutations are likely to be early clonal events and confer poor prognosis.

Histone methyltransferases (HMTs) are important epigenetic regulators of gene transcription and have been found disrupted at the genomic level in a spectrum of human tumors including hematological malignancies. In CLL, recurring genomic lesions targeting chromatin modifiers are emerging in the literature (Puente 2015, Nature) but their biological a...

Chronic lymphocytic leukemia (CLL) is a paradigmatic malignancy where the interplay of cell-extrinsic and cell-intrinsic factors has a major impact on disease evolution. Indeed, extrinsic triggering, e.g. antigenic stimulation through the B-cell receptor (BcR), together with intrinsic aberrations, e.g. accumulation of genetic defects, play a major...

Alterations in the expression of TP63, a TP53 gene family member, are known to critically affect tumorigenesis though the gene is almost never mutated. In cancer, the following two TP63 isoforms have been extensively studied with contrasting/opposite functions: DNp63, known to promote oncogenesis, and TAp63, which instead has been shown to promote...

Chronic lymphocytic leukemia (CLL) leukemic cells express B-cell receptor immunoglobulin (BcR IG) whose signaling is of paramount importance throughout the natural history of the disease. Indeed, signaling pathways downstream of the BcR are constitutively active in all cases of CLL and inhibitors of the Bruton's tyrosine kinase BTK (Ibrutinib) or P...

Chronic Lymphocytic Leukemia (CLL) is characterized by aberrant methylation patterns. In this study we showed differential methylation profiles between cases belonging to stereotyped subset #6 and #8. The analysis revealed TP63 as a differentially express gene which acts as a prosurvival factor for CLL cells.

Recent studies on splenic marginal zone lymphoma identified distinct mutations in genes belonging to the B-cell receptor and Toll-like receptor signaling pathways, thus pointing to their potential implication in the biology of the disease. However, limited data is available regarding the exact role of TLR. We aimed at characterizing the expression...

Subset #8 is a distinctive subset of patients with chronic lymphocytic leukemia (CLL) defined by the expression of stereotyped IGHV4-39/IGKV1(D)-39 B-cell receptors. Subset #8 patients experience aggressive disease and exhibit the highest risk for Richter's transformation among all CLL. In order to obtain biological insight into this behavior, we p...

EZH2 is the enzymatic subunit of the polycomb repressive complex 2 (PRC2), which induces gene repression through trimethylation of histone H3 at lysine 27 (H3K27me3). EZH2 over-expression has been reported in a broad range of hematopoietic and solid malignancies and associated with poor prognosis. Recently, we reported for the first time that EZH2...

We recently reported that chronic lymphocytic leukemia (CLL) subgroups with distinct clonotypic BCRs present discrete patterns of TLR expression, function, and/or tolerance. In this study, to explore whether specific types of BCR/TLR collaboration exist in CLL, we studied the effect of single versus concomitant BCR and/or TLR stimulation on CLL cel...

Mounting evidence suggests that specific modalities of B-cell receptor (BcR) and Toll-like receptor (TLR) collaboration and/or regulation may exist in chronic lymphocytic leukemia (CLL), eventually impacting on the behavior of the malignant clones. CLL patients assigned to stereotyped subset #4 (mutated IGHV4-34/IGKV2-30 BcRs, SS4), the largest sub...

The chromatin modifier EZH2 is overexpressed and associated with inferior outcome in mantle cell lymphoma (MCL). Recently, we demonstrated preferential DNA methylation of HOX genes in MCL compared with chronic lymphocytic leukemia (CLL), despite these genes not being expressed in either entity. Since EZH2 has been shown to regulate HOX gene express...

Nowadays, chronic lymphocytic leukemia (CLL) is considered as a prototypic antigen-driven lymphoma, with antigenic stimuli from the microenvironment promoting tumor outgrowth. Antigen recognition is a function of both the clonotypic B cell receptor immunoglobulin (BcR IG) and various other immune sensors, e.g., the Toll-like receptors. The critical...

Gene pathway identification is an open and active research area that has attracted the interest not only of biomedical scientists but also of a large number of researchers from disciplines related to knowledge discovery from biological data. In this paper, we used Structural Equation Modeling (SEM) in order to statistically investigate the Toll-Lik...

Critical processes of B-cell physiology, including immune signaling through the B-cell receptor (BcR) and/or Toll-like receptors (TLRs), are targeted by microRNAs. With this in mind and also given the important role of BcR and TLR signaling and microRNAs in chronic lympocytic leukemia (CLL), we investigated whether microRNAs could be implicated in...

561 Mounting evidence suggests that the molecular classification of CLL into subsets with stereotyped B cell receptors (BcRs) is functionally and clinically relevant. In fact, cases of the same subset can share not only BcR sequence motifs but also biological and clinical features as well. This suggests that the functional antigen reactivity profil...

3862 Subgroups of CLL cases defined on the basis of the immunogenetic features of their B cell receptors (BcRs), especially those cases belonging to subsets with stereotyped BcRs, exhibit differential responses to immune stimulation through either the BcR or the Toll-Like Receptors (TLRs). This indicates distinct, subset-biased modalities of BcR co...

Chronic lymphocytic leukemia (CLL) can be divided into prognostic subgroups based on the IGHV gene mutational status, and is further characterized by multiple subsets of cases with quasi-identical or stereotyped B cell receptors that also share clinical and biological features. We recently reported differential DNA methylation profiles in IGHV-muta...

Subgroups of patients with chronic lymphocytic leukemia (CLL) have distinct expression profiles of Toll-like receptor (TLR) pathway-associated genes. To test the hypothesis that signaling through innate immunity receptors may influence the behavior of the malignant clone, we investigated the functional response triggered by the stimulaton of Toll-l...

Signaling through the B-cell receptor appears to be a major contributor to the pathogenesis of chronic lymphocytic leukemia. Toll-like receptors bridge the innate and adaptive immune responses by acting as co-stimulatory signals for B cells. The available data on the expression of Toll-like receptors in chronic lymphocytic leukemia are limited and...

374 Mature B cells recognize antigens through the B cell receptor (BCR) in a specific way and through innate immunity receptors, such as the Toll-like receptors (TLRs) and Nod-like receptors (NLRs), in a costimulatory manner. Signaling through the BCR appears to be a major contributing factor in CLL development and, perhaps, evolution. However, the...

44 The role of antigen in the development of CLL is underscored by the biased immunoglobulin (IG) gene repertoire expressed by the malignant clones, the prognostic implications of B-cell receptor (BcR) structure and the identification of subsets of patients with quasi-identical, stereotyped BcRs. The structural homology of BcRs implies a role for a...