| 1. |
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| 2. |
- Chatzouli, Maria, et al.
(författare)
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Heterogeneous Functional Effects of Concomitant B Cell Receptor and TLR Stimulation in Chronic Lymphocytic Leukemia with Mutated versus Unmutated Ig Genes
- 2014
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Ingår i: Journal of Immunology. - : The American Association of Immunologists. - 0022-1767 .- 1550-6606. ; 192:10, s. 4518-4524
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Tidskriftsartikel (refereegranskat)abstract
- 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 cells from mutated (M-CLL) and unmutated CLL (U-CLL) cases. We stimulated negatively isolated CLL cells by using anti-IgM, imiquimod, and CpG oligodeoxynucleotide for BCR, TLR7, and TLR9, respectively, alone or in combination for different time points. After in vitro culture in the absence of stimulation, differences in p-ERK were identified at any time point, with higher p-ERK levels in U-CLL versus M-CLL. Pronounced p-ERK induction was seen by single stimulation in U-CLL, whereas BCR/TLR synergism was required in M-CLL, in which the effect was overall limited in scale. An opposite pattern was observed regarding induction of apoptosis, as studied by Western blotting for the cleaved fragment of poly(ADP-ribose) polymerase, and the active isoform of caspase-8, with M-CLL responding even to single stimulation, contrasting with U-CLL that showed minimal response. Our findings suggest that concomitant engagement of BCR and TLR leads to differential responses in CLL depending on the mutational status of the BCR. Differential intensity and duration of responses in M-CLL versus U-CLL indicates that the differences in signal transduction between the two subgroups may be primarily quantitative rather than qualitative.
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| 3. |
- Ghia, Paolo, et al.
(författare)
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Crystallographic evidence of autologous recognition by a clonotypic B cell receptor in chronic lymphocytic leukemia
- 2015
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Ingår i: Leukemia and Lymphoma. - IRCCS Sci Inst San Raffaele, Div Expt Oncol, Milan, Italy. [Degano, Massimo] IRCCS Sci Inst San Raffaele, Dept Immunol Transplantat & Infect Dis, Biocrystallog Unit, Milan, Italy. [Duehren-von Minden, Marcus; Schneider, Dunja; Alkhatib, Alabbas] Univ Freiburg, Ctr Biol Signaling Studies, Fac Biol, D-79106 Freiburg, Germany. [Belhart, Rudolf; Jumaa, Hassan] Univ Ulm Klinikum, Ulm, Germany. [Ntoufa, Stavroula; Stamatopoulos, Kostas] Ctr Res & Technol, Inst Appl Biosci, Thessaloniki, Greece. [Chiorazzi, Nicholas] Feinstein Inst Med Res, Manhasset, NY USA. [Stamatopoulos, Kostas] Uppsala Univ, Dept Immunol Genet & Pathol, Uppsala, Sweden. [Ghia, Paolo] Univ Milan, Osped San Raffaele, Dept Oncohematol, I-20127 Milan, Italy. [Ghia, Paolo] Univ Vita Salute San Raffaele, Milan, Italy.. - 1042-8194 .- 1029-2403. ; 56:S1, s. 110-111
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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| 4. |
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| 5. |
- Gounari, Maria, et al.
(författare)
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Excessive antigen reactivity may underlie the clinical aggressiveness of chronic lymphocytic leukemia stereotyped subset #8
- 2015
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Ingår i: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 125:23, s. 3580-3587
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Tidskriftsartikel (refereegranskat)abstract
- 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 transformation among all CLL. In order to obtain biological insight into this behavior, we profiled the antigen reactivity and signaling capacity of subset #8 vs other clinically aggressive stereotyped subsets, namely subsets #1 and #2. Twenty-seven monoclonal antibodies (mAbs) from subsets #1, #2, and #8 CLL clones were prepared as recombinant human immunoglobulin G1 and used as primary antibodies in enzyme-linked immuno-sorbent assays against representatives of the major classes of established antigenic targets for CLL. Subset #8 CLL mAbs exhibited broad polyreactivity as they bound to all antigens tested, in clear contrast with the mAbs from the other subsets. Antigen challenge of primary CLL cells indicated that the promiscuous antigen-binding activity of subset #8 mAbs could lead to significant cell activation, again in contrast to the less responsive CLL cells from subsets #1 and #2. These features constitute a distinctive profile for CLL subset #8, supporting the existence of distinct mechanisms of aggressiveness in different immunogenetic subsets of CLL.
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| 6. |
- Kanduri, Meena, 1974, et al.
(författare)
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A key role for EZH2 in epigenetic silencing of HOX genes in mantle cell lymphoma
- 2013
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Ingår i: Epigenetics. - : Informa UK Limited. - 1559-2294 .- 1559-2308. ; 8:12, s. 1280-8
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Tidskriftsartikel (refereegranskat)abstract
- 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 expression, to gain further insight into its possible role in differential silencing of HOX genes in MCL vs. CLL, we performed detailed epigenetic characterization using representative cell lines and primary samples. We observed significant overexpression of EZH2 in MCL vs. CLL. Chromatin immune precipitation (ChIP) assays revealed that EZH2 catalyzed repressive H3 lysine 27 trimethylation (H3K27me3), which was sufficient to silence HOX genes in CLL, whereas in MCL H3K27me3 is accompanied by DNA methylation for a more stable repression. More importantly, hypermethylation of the HOX genes in MCL resulted from EZH2 overexpression and subsequent recruitment of the DNA methylation machinery onto HOX gene promoters. The importance of EZH2 upregulation in this process was further underscored by siRNA transfection and EZH2 inhibitor experiments. Altogether, these observations implicate EZH2 in the long-term silencing of HOX genes in MCL, and allude to its potential as a therapeutic target with clinical impact.
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| 7. |
- Kanduri, Meena, 1974, et al.
(författare)
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Distinct transcriptional control in major immunogenetic subsets of chronic lymphocytic leukemia exhibiting subset-biased global DNA methylation profiles.
- 2012
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Ingår i: Epigenetics. - : Informa UK Limited. - 1559-2294 .- 1559-2308. ; 7:12, s. 1435-42
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Tidskriftsartikel (refereegranskat)abstract
- 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-mutated and IGHV-unmutated CLL subgroups. For the first time, we here explore the global methylation profiles of stereotyped subsets with different prognosis, by applying high-resolution methylation arrays on CLL samples from three major stereotyped subsets: the poor-prognostic subsets #1 (n = 15) and #2 (n = 9) and the favorable-prognostic subset #4 (n = 15). Overall, the three subsets exhibited significantly different methylation profiles, which only partially overlapped with those observed in our previous study according to IGHV gene mutational status. Specifically, gene ontology analysis of the differentially methylated genes revealed a clear enrichment of genes involved in immune response, such as B cell activation (e.g., CD80, CD86 and IL10), with higher methylation levels in subset #1 than subsets #2 and #4. Accordingly, higher expression of the co-stimulatory molecules CD80 and CD86 was demonstrated in subset #4 vs. subset #1, pointing to a key role for these molecules in the crosstalk of CLL subset #4 cells with the microenvironment. In summary, investigation of three prototypic, stereotyped CLL subsets revealed distinct DNA methylation profiles for each subset, which suggests subset-biased patterns of transcriptional control and highlights a key role for epigenetics during leukemogenesis.
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| 8. |
- Kontopoulos, Efstratios, et al.
(författare)
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Studying the Cohesion Evolution of Genes Related to Chronic Lymphocytic Leukemia Using Semantic Similarity in Gene Ontology and Self-Organizing Maps
- 2016
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Ingår i: Proceedings of SWAT4LS-16, 9th International Conference on Semantic Web Applications and Tools for Life Sciences.
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Konferensbidrag (refereegranskat)abstract
- 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 genetic landscape of chronic lymphocytic leukemia (CLL), the most common adult leukemia. CLL displays remarkable clinical heterogeneity, likely reflecting its underlying biological heterogeneity which, despite all progress, still remains insufficiently characterized and understood. This paper deploys an ontology-based semantic similarity combined with self-organizing maps for studying the temporal evolution of cohesion among CLL-related genes and the extracted information. Three consecutive time periods are considered and groups of genes are derived therein. Our preliminary results indicated that our proposed gene groupings are meaningful and that the temporal dimension indeed impacted the gene cohesion, leaving a lot of room for further promising investigations.
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| 9. |
- Ljungström, Viktor, et al.
(författare)
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Whole-exome sequencing in relapsing chronic lymphocytic leukemia : clinical impact of recurrent RPS15 mutations
- 2016
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Ingår i: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 127:8, s. 1007-1016
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Tidskriftsartikel (refereegranskat)abstract
- Fludarabine, cyclophosphamide and rituximab (FCR) is first-line treatment for medically fit chronic lymphocytic leukemia (CLL) patients, however despite good response rates many patients eventually relapse. Whilst recent high-throughput studies have identified novel recurrent genetic lesions in adverse-prognostic CLL, the mechanisms leading to relapse after FCR therapy are not completely understood. To gain insight into this issue, we performed whole-exome sequencing of sequential samples from 41 CLL patients who were uniformly treated with FCR but relapsed after a median of 2 years. In addition to mutations with known adverse-prognostic impact (TP53, NOTCH1, ATM, SF3B1, NFKBIE, BIRC3) a large proportion of cases (19.5%) harbored mutations in RPS15, a gene encoding a component of the 40S ribosomal subunit. Extended screening, totaling 1119 patients, supported a role for RPS15 mutations in aggressive CLL, with one-third of RPS15-mutant cases also carrying TP53 aberrations. In most cases selection of dominant, relapse-specific subclones was observed over time. However, RPS15 mutations were clonal prior to treatment and remained stable at relapse. Notably, all RPS15 mutations represented somatic missense variants and resided within a 7 amino-acid evolutionarily conserved region. We confirmed the recently postulated direct interaction between RPS15 and MDM2/MDMX and transient expression of mutant RPS15 revealed defective regulation of endogenous p53 compared to wildtype RPS15. In summary, we provide novel insights into the heterogeneous genetic landscape of CLL relapsing after FCR treatment and highlight a novel mechanism underlying clinical aggressiveness involving a mutated ribosomal protein, potentially representing an early genetic lesion in CLL pathobiology.
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| 10. |
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| 11. |
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| 12. |
- Mansouri, Larry, et al.
(författare)
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NF-kappa B activation in chronic lymphocytic leukemia : A point of convergence of external triggers and intrinsic lesions
- 2016
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Ingår i: Seminars in Cancer Biology. - : Elsevier BV. - 1044-579X .- 1096-3650. ; 39, s. 40-48
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Forskningsöversikt (refereegranskat)abstract
- The nuclear factor-kappa B (NF-kappa B) 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-kappa B activation have been identified in CLL (i.e. BIRC3, MYD88 and NFKBIE mutations) and often at a low frequency. On the other hand, CLL B cells seem 'addicted' to the tumor microenvironment for their survival and proliferation, which is primarily mediated by interaction through a number of cell surface receptors, e.g. the B-cell receptor (BcR), Toll-like receptors and CD40, that in turn activate downstream NF-kappa B. The importance of cell-extrinsic triggering for CLL pathophysiology was recently also highlighted by the clinical efficacy of novel drugs targeting microenvironmental interactions through the inhibition of BcR signaling. In other words, CLL can be considered a prototype disease for studying the intricate interplay between external triggers and intrinsic aberrations and their combined impact on disease evolution. In this review, we will discuss the current understanding of mechanisms underlying NF-kappa B deregulation in CLL, including micro-environmental, genetic and epigenetic events, and summarize data generated in murine models resembling human CLL. Finally, we will also discuss different strategies undertaken to intervene with the NF-kappa B pathway and its upstream mediators.
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| 13. |
- Minici, Claudia, et al.
(författare)
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Distinct homotypic B-cell receptor interactions shape the outcome of chronic lymphocytic leukaemia
- 2017
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- 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 that are specific for each subgroup of patients with homogeneous clinicobiological profiles. The molecular details of the BcR-BcR interactions apparently dictate the clinical course of disease, with stronger affinities and longer half-lives in indolent cases, and weaker, short-lived contacts mediating the aggressive ones. The diversity of homotypic BcR contacts leading to cell-autonomous signalling reconciles the existence of a shared pathogenic mechanism with the biological and clinical heterogeneity of CLL and offers opportunities for innovative treatment strategies.
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| 14. |
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| 15. |
- Ntoufa, Stavroula, et al.
(författare)
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B Cell Anergy Modulated by TLR1/2 and the miR-17 similar to 92 Cluster Underlies the Indolent Clinical Course of Chronic Lymphocytic Leukemia Stereotyped Subset #4
- 2016
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Ingår i: Journal of Immunology. - : The American Association of Immunologists. - 0022-1767 .- 1550-6606. ; 196:10, s. 4410-4417
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Tidskriftsartikel (refereegranskat)abstract
- 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 experimental evidence that subset #4 CLL cells show low IgG levels, constitutive ERK1/2 activation, and fail to either release intracellular Ca2+ or activate MAPK signaling after BCR cross-linking, thus displaying a signature of B cell anergy at both biochemical and functional levels. Interestingly, TLR1/2 triggering restored BCR functionality, likely breaching the anergic state, and this was accompanied by induction of the miR17 similar to 92 cluster, whose members target critical BCR-associated molecules, including MAPKs. In conclusion, we demonstrate BCR anergy in CLL subset #4 and implicate TLR signaling and the miR-17 similar to 92 cluster in the regulation of the anergic state. This detailed signaling profiling of subset #4 has implications for advanced understanding of the complex regulation of intracellular signaling pathways in CLL, currently a major therapeutic target of the disease.
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| 16. |
- Ntoufa, Stavroula, et al.
(författare)
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Toll-like receptors signaling : A complex network for in B-cell lymphoid malignancies NF-kappa B activation
- 2016
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Ingår i: Seminars in Cancer Biology. - : Elsevier BV. - 1044-579X .- 1096-3650. ; 39, s. 15-25
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Forskningsöversikt (refereegranskat)abstract
- 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, including the Toll-like receptors (TLRs), eliciting a range of cellular responses, including proliferation but also anergy and apoptosis, often with disease-specific patterns. Critically, the TLR signaling pathways are intertwined with other receptor pathways in malignant B cells, most notably the B-cell receptor pathway, and converge on NF-kappa B, leading to its activation. In the present review, we summarize the literature on TLR expression and functionality and its impact on NF-kappa B activation in different B cell malignancies including chronic lymphocytic leukemia where TLR9 induces activation, cell proliferation and chemoresistance in a proportion of patients while apoptosis can be induced in others. Additionally, we also discuss the therapeutic potential of strategies targeting TLR signaling in lymphoma.
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| 17. |
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| 18. |
- Papakonstantinou, Nikos, et al.
(författare)
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Integrated epigenomic and transcriptomic analysis reveals TP63 as a novel player in clinically aggressive chronic lymphocytic leukemia
- 2019
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Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 144:11, s. 2695-2706
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Tidskriftsartikel (refereegranskat)abstract
- 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 divergent clinical behavior are not fully elucidated. To gain insight into this issue, here we focused on epigenomic signatures and their links with gene expression, particularly investigating genome-wide DNA methylation profiles in subsets #6 and #8 as well as other U-CLL cases not expressing stereotyped BcR IG. We found that subset #8 showed a distinctive DNA methylation profile compared to all other U-CLL cases, including subset #6. Integrated analysis of DNA methylation and gene expression revealed significant correlation for several genes, particularly highlighting a relevant role for the TP63 gene which was hypomethylated and overexpressed in subset #8. This observation was validated by quantitative PCR, which also revealed TP63 mRNA overexpression in additional nonsubset U-CLL cases. BcR stimulation had distinct effects on p63 protein expression, particularly leading to induction in subset #8, accompanied by increased CLL cell survival. This pro-survival effect was also supported by siRNA-mediated downregulation of p63 expression resulting in increased apoptosis. In conclusion, we report that DNA methylation profiles may vary even among CLL patients with similar somatic hypermutation status, supporting a compartmentalized approach to dissecting CLL biology. Furthermore, we highlight p63 as a novel prosurvival factor in CLL, thus identifying another piece of the complex puzzle of clinical aggressiveness. What's new? In chronic lymphocytic leukemia (CLL), cases with unmutated immunoglobulin receptors (U-CLL) are generally associated with inferior outcome, albeit still displaying considerable heterogeneity. Might such differences in CLL progression be explained by epigenetics? In this study, the authors found that an unusually aggressive subset of CLLs called subset #8 has a distinctive DNA-methylation profile. They also found that p63 is a novel pro-survival factor for CLL cells. These molecular studies may lead to new prognostic biomarkers, and possibly new therapeutic targets, for CLL.
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| 19. |
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| 20. |
- Papakonstantinou, Nikos, et al.
(författare)
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The histone methyltransferase EZH2 as a novel prosurvival factor in clinically aggressive chronic lymphocytic leukemia
- 2016
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Ingår i: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 7:24, s. 35946-35959
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Tidskriftsartikel (refereegranskat)abstract
- 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 unmutated IGHV genes (U-CLL) displayed significantly higher EZH2 expression compared to indolent CLL cases with mutated IGHV genes (M-CLL); furthermore, in U-CLL EZH2 expression was upregulated with disease progression. Within U-CLL, EZH2(high) cases harbored significantly fewer (p = 0.033) TP53 gene abnormalities compared to EZH2(low) cases. EZH2(high) cases displayed high H3K27me3 levels and increased viability suggesting that EZH2 is functional and likely confers a survival advantage to CLL cells. This argument was further supported by siRNA-mediated downmodulation of EZH2 which resulted in increased apoptosis. Notably, at the intraclonal level, cell proliferation was significantly associated with EZH2 expression. Treatment of primary CLL cells with EZH2 inhibitors induced downregulation of H3K27me3 levels leading to increased cell apoptosis. In conclusion, EZH2 is overexpressed in adverse-prognosis CLL and associated with increased cell survival and proliferation. Pharmacologic inhibition of EZH2 catalytic activity promotes apoptosis, highlighting EZH2 as a novel potential therapeutic target for specific subgroups of patients with CLL.
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| 21. |
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| 22. |
- Rosenquist, Richard, et al.
(författare)
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Genome-Wide DNA Methylation Profiling of Chronic Lymphocytic Leukemia Subsets Carrying Stereotyped B Cell Receptors
- 2017
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Ingår i: Blood. - 0006-4971. ; 130:Suppl 1, s. 57-57
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- In recent years, subsets of chronic lymphocytic leukemia (CLL) patients carrying quasi-identical or stereotyped B cell receptors (BcRs) have been identified that share clinicobiological features and disease outcome. While these stereotyped subsets show distinct gene expression and genomic profiles, the DNA methylation landscape remains largely unexplored. By applying high-resolution 450K methylation arrays, we investigated 176 CLL subset cases belonging to: (i) the clinically aggressive, IGHV-unmutated (U-CLL) subsets $$1 (clan I genes/IGKV(D)1-39, n=37) and $$8 (IGHV4-39/IGKV1(D)-39, n=21); (ii) the IGHV1-69-expressing U-CLL subsets $$3 (n=12), $$5 (n=9), $$6 (n=22), and $$7 (n=12); and, (iii) the indolent, IGHV-mutated (M-CLL) subset $$4 (IGHV4-34/IGKV2-30, n=28). In addition, we included subset $$2 cases (IGHV3-21/IGLV3-21, mixed mutation status, n=35) that have a poor outcome independent of IGHV mutation status. For comparative purposes, we included a cohort of CLL cases that do not express stereotyped BcRs ('non-subset', n=325). These patients were subgrouped according to the recently proposed epigenetic classification of CLL, i.e. poor-prognostic, naive-like CLL (n-CLL, n=102), favorable-prognostic, memory-like CLL (m-CLL; n=176), broadly corresponding to U-CLL and M-CLL, respectively, and a third intermediate CLL subgroup (i-CLL; n=47), which express borderline mutated IGHV genes and have an intermediate prognosis. Finally, a series of sorted normal subpopulations spanning different stages of B-cell differentiation [precursors (n=22), naive B cells (n=19) and germinal center/memory B-cells (n=33)] were also included in the analysis. Overall, unsupervised analysis of subset vs. non-subset CLL revealed that all U-CLL subsets clustered with n-CLL, subset $$4 clustered with m-CLL, while subset $$2 clustered separately with i-CLL (Figure 1). Supervised analysis revealed a limited number of CpG sites that were differentially methylated when comparing each U-CLL or M-CLL subset with non-subset cases. In contrast, almost all subset $$2 cases clustered separately from i-CLL in supervised analysis, indicating that this subset might represent a distinct subgroup of i-CLL. We recently demonstrated that the number of epigenetic changes that a tumor acquires, compared to its cellular origin (i.e. 'epigenetic burden'), may be a powerful predictor of clinical aggressiveness (Queiros et al, Cancer Cell 2016). When adopting this approach in CLL, comparison of specific subsets vs. their non-subset cases matched by epigenetic subgroup, revealed significant differences in the epigenetic burden amongst the various groupings; for instance, in subset $$1 vs. n-CLL (72K vs. 67K, plt;0.05) and in subset $$2 vs. i-CLL (76K vs. 68K, p=0.001), while no difference was observed between subset $$4 vs. m-CLL (83K vs. 82K, p=not significant). Subset $$2 cases frequently carry del(11q) and harbor SF3B1 mutations, however, neither the IGHV mutation status nor the presence of del(11q) or SF3B1 mutations had any impact on the epigenetic burden within subset $$2. In conclusion, U-CLL and M-CLL subsets generally clustered with n-CLL and m-CLL categories, respectively, implying common cellular origins. In contrast, subset $$2 emerged as the first defined member of the i-CLL group, which in turn alludes to a distinct cellular origin and/or pathogenetic process for subset $$2 and i-CLL patients.Disclosures Papakonstantinou: Janssen Pharmaceuticals: Research Funding; Gilead: Research Funding. Smedby: Janssen: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees. Gaidano: Roche: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Ghia: AbbVie: Consultancy; Adaptive: Consultancy; Gilead: Consultancy, Research Funding, Speakers Bureau; Janssen: Consultancy, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy; Roche: Consultancy; Novartis: Research Funding. Stamatopoulos: Novartis SA: Research Funding; Gilead: Consultancy, Honoraria, Research Funding; Janssen Pharmaceuticals: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding.↵* Asterisk with author names denotes non-ASH members.
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| 23. |
- Vilia, Maria Giovanna, et al.
(författare)
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The inhibitory receptor toll interleukin-1R 8 (TIR8/IL-1R8/SIGIRR) is downregulated in chronic lymphocytic leukemia
- 2017
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Ingår i: Leukemia and Lymphoma. - : Taylor & Francis. - 1042-8194 .- 1029-2403. ; 58:10, s. 2419-2425
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Tidskriftsartikel (refereegranskat)abstract
- 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 leukemia (CLL), supporting its role as a novel tumor restrainer. The aim of this study was to measure the amount of TIR8 mRNA and protein in CLL cells, and to analyze its regulation of expression. Circulating leukemic cells expressed lower levels of TIR8 compared to normal B-lymphocytes. Treatment of CLL cells with Azacytidine restored higher levels of TIR8 suggesting that DNA methylation may be involved in modulating TIR8 expression, with implications for novel therapeutic strategies.
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| 24. |
- Xochelli, Aliki, et al.
(författare)
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Chronic Lymphocytic Leukemia with Mutated IGHV4-34 Receptors : Shared and Distinct Immunogenetic Features and Clinical Outcomes
- 2017
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Ingår i: Clinical Cancer Research. - 1078-0432 .- 1557-3265. ; 23:17, s. 5292-5301
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: We sought to investigate whether B cell receptor immunoglobulin (BcR IG) stereotypy is associated with particular clinicobiological features among 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 Design: In a series of 19,907 CLL cases with available immunogenetic information, we identified 339 IGHV4-34expressing cases assigned to one of the four largest stereotyped M-CLL subsets, namely subsets #4, #16, #29 and #201, and investigated in detail their clinicobiological characteristics and disease outcomes. Results: We identified shared and subset-specific patterns of somatic hypermutation (SHM) among patients assigned to these subsets. The greatest similarity was observed between subsets #4 and #16, both including IgG-switched cases (IgG-CLL). In contrast, the least similarity was detected between subsets #16 and #201, the latter concerning IgM/D-expressing CLL. Significant differences between subsets also involved disease stage at diagnosis and the presence of specific genomic aberrations. IgG subsets #4 and #16 emerged as particularly indolent with a significantly (P < 0.05) longer time-to-first-treatment (TTFT; median TTFT: not yet reached) compared with the IgM/D subsets #29 and #201 (median TTFT: 11 and 12 years, respectively). Conclusions: Our findings support the notion that BcR IG stereotypy further refines prognostication in CLL, superseding the immunogenetic distinction based solely on SHM load. In addition, the observed distinct genetic aberration landscapes and clinical heterogeneity suggest that not all M-CLL cases are equal, prompting further research into the underlying biological background with the ultimate aim of tailored patient management.
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