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Antonella Zucchetto - One of the best experts on this subject based on the ideXlab platform.
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cd49d is the strongest flow cytometry based predictor of overall survival in chronic lymphocytic leukemia
Journal of Clinical Oncology, 2014Co-Authors: Pietro Ulia, Antonella Zucchetto, Tai D Shanafel, Christophe Fega, Lilla Cro, Holge Nuckel, Luca Aldini, Antonina V Kurtova, Alessandra Ferrajoli, Ja A UrgeAbstract:Purpose Although CD49d is an unfavorable prognostic marker in chronic lymphocytic leukemia (CLL), definitive validation evidence is lacking. A worldwide multicenter analysis was performed using published and unpublished CLL series to evaluate the impact of CD49d as an overall (OS) and treatment-free survival (TFS) predictor. Patients and Methods A training/validation strategy was chosen to find the optimal CD49d cutoff. The hazard ratio (HR) for death and treatment imposed by CD49d was estimated by pooled analysis of 2,972 CLLs; Cox analysis stratified by center and stage was used to adjust for confounding variables. The importance of CD49d over other flow cytometry–based prognosticators (eg, CD38, ZAP-70) was ranked by recursive partitioning. Results Patients with ≥ 30% of neoplastic cells expressing CD49d were considered CD49d+. Decrease in OS at 5 and 10 years among CD49d+ patients was 7% and 23% (decrease in TFS, 26% and 25%, respectively). Pooled HR of CD49d for OS was 2.5 (2.3 for TFS) in univariate...
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cd49d is the strongest flow cytometry based predictor of overall survival in chronic lymphocytic leukemia
Blood, 2013Co-Authors: Pietro Ulia, Antonella Zucchetto, Tai D Shanafel, Christophe Fega, Lilla Cro, Holge Nuckel, Luca Aldini, Antonina V Kurtova, Alessandra Ferrajoli, Ja A UrgeAbstract:![Graphic][1] Purpose Although CD49d is an unfavorable prognostic marker in chronic lymphocytic leukemia (CLL), definitive validation evidence is lacking. A worldwide multi-center analysis was performed using published and unpublished CLL series to evaluate the impact of CD49d as overall survival (OS) and treatment free survival (TFS) predictor. Patients and Methods A training/validation strategy was chosen to find the optimal CD49d cut-off. The hazard ratio (HR) for death and treatment imposed by CD49d was estimated by pooled analysis of 2,972 CLL, and Cox analysis stratified by center and stage was used to adjust for confounding variables. The importance of CD49d over other flow cytometry-based prognosticators (CD38, ZAP-70) was ranked by recursive partitioning. Results Patients with ≥30% of neoplastic cells expressing CD49d were considered CD49d+. The decrease in OS at 5 and 10-years among CD49d+ cases was 7% and 23% (decrease in TFS 26% and 25% respectively). The pooled HR of CD49d for OS was 2.5 (2.3 for TFS) in univariate analysis. This HR remained significant and of similar magnitude (HR=2.0) in a Cox model adjusted for clinical and biological prognosticators. Hierarchical trees including all cases, or restricted to early stage or patients ≤65 years, always selected CD49d as the most important flow-cytometry-based biomarker, with negligible additional prognostic information added by CD38 or ZAP-70. Consistently, by bivariate analysis, CD49d reliably identified patients' subsets with poorer outcome independent of CD38 and ZAP-70. Conclusions In this analysis of ∼3000 patients, CD49d emerged as the strongest flow cytometry-based predictor of OS and TFS in CLL. Disclosures: Shanafelt: Genentech: Research Funding; Glaxo-Smith-Kline: Research Funding; Cephalon: Research Funding; Hospira: Research Funding; Celgene: Research Funding; Polyphenon E International: Research Funding. Burger: Pharmacyclics: Research Funding. [1]: /embed/inline-graphic-2.gif
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CD49d is overexpressed by trisomy 12 chronic lymphocytic leukemia cells: evidence for a methylation-dependent regulation mechanism.
Blood, 2013Co-Authors: Antonella Zucchetto, Riccardo Bomben, Francesca Rossi, Dania Benedetti, Chiara Caldana, Erika Tissino, Michele Dal Bo, Evelyn Hutterer, Federico Pozzo, Giovanni D'arenaAbstract:CD49d is a negative prognosticator in chronic lymphocytic leukemia (CLL), expressed by ~40% of CLL cases, and associated with aggressive and accelerated clinical courses. In the present study, analyzing CD49d expression in a wide CLL cohort (n=1200) belonging to different cytogenetic groups, we report that trisomy 12 CLL almost universally expressed CD49d, and were characterized by the highest CD49d expression levels among all CD49d + CLL. Through bisulfite genomic sequencing, we demonstrated that while CD49d + /trisomy12 CLL almost completely lacked methylation of the CD49d gene, CD49d - /no trisomy12 CLL were overall methylated, the methylation levels being inversely correlated to CD49d expression (p=0.0001). Consistently, CD49d expression was recovered in CD49d - hypermethylated CLL cells upon in-vitro treatment with the hypomethylating agent 5-aza-29-deoxycytidine. These findings may contribute to explain the clinico-biological features of trisomy 12 CLL, including the high rates of cell proliferation and disease progression, lymph node involvement and predisposition to Richter9s syndrome transformation.
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CD49d Is Overexpressed in Trisomy 12 Chronic Lymphocytic Leukemia by an Epigenetic-Dependent Transcriptional Control
Blood, 2012Co-Authors: Antonella Zucchetto, Riccardo Bomben, Francesca Rossi, Davide Rossi, Dania Benedetti, Chiara Caldana, Erika Tissino, Michele Dal Bo, Francesco Zaja, Gabriele PozzatoAbstract:Abstract 929 CD49d is an adhesion molecule with a variable expression in chronic lymphocytic leukemia (CLL). Only one third of CLL display CD49d expression in a significant fraction of cells, the remaining cases either expressing very low levels or completely lacking its expression. The negative prognostic impact of CD49d in CLL and its key role in microenvironmental interactions have been broadly described by several studies, whereas information on the mechanisms regulating CD49d expression in CLL is still lacking. Aiming to understand the genetic mechanisms underlying the different expression pattern of CD49d in CLL, CD49d expression was investigated by flow cytometry in the neoplastic component of 972 CLL patients, and correlated with cytogenetic profiles assessed by fluorescence in situ hybridization (FISH). Using the 30% positive cut-off value, 603 cases (62%) were CD49d-, whereas 369 cases (38%) were CD49d+. Correlation of CD49d expression with the major cytogenetic alterations (del13q14.3, trisomy 12, del11q22-q23-, del17p13.1), highlighted a very strong association between CD49d expression and the presence of trisomy 12 (p 99% purity) CD49d- and CD49d+ components from 3 CLL cases characterized by both CD49d bimodal expression (27%, 57%, and 75% of CD49d positive cells), and the presence of trisomy 12 in a fraction of the cells (25%, 42% and 63% respectively). In all cases, the CD49d- components almost completely lacked trisomy 12 (5%, 4%, and 0%), whereas the CD49d+ fractions displayed 70%, 62%, and 75% of trisomy 12, respectively (p A gene expression profiling was performed comparing CD49d+/trisomy12 (n=5) versus CD49d-/normal FISH CLL (n=5). According to bioinformatics tools for global analysis of gene function, the “Chromatin modification” (p Altogether, our results demonstrate that the overall down-regulated CD49d expression characterizing CLL is subjected to epigenetic control. Re-expression of CD49d may occur through a fine regulation of methyltransferase and chromatin modification processes, particularly active in trisomy 12 CLL, where CD49d expression may have a role in determining the clinical and biological features of this particular CLL subset. Disclosures: No relevant conflicts of interest to declare.
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the cd49d cd29 complex is physically and functionally associated with cd38 in b cell chronic lymphocytic leukemia cells
Leukemia, 2012Co-Authors: Antonella Zucchetto, D Benedetti, Riccardo Bomben, Davide Rossi, Erika Tissino, Tiziana Vaisitti, Valeria Bertagnolo, M. I. Del Principe, A. Gorgone, Gabriele PozzatoAbstract:CD49d and CD38 are independent negative prognostic markers in chronic lymphocytic leukemia (CLL). Their associated expression marks a disease subset with a highly aggressive clinical course. Here, we demonstrate a constitutive physical association between the CD49d/CD29 integrin complex and CD38 in primary CLL cells and B-cell lines by (i) cocapping, (ii) coimmunoprecipitation and (iii) cell adhesion experiments using CD49d-specific substrates (vascular-cell adhesion molecule-1 or CS-1/H89 fibronectin fragments). The role of CD38 in CD49d-mediated cell adhesion was studied in CD49d(+)CD38(+) and CD49d(+)CD38(-) primary CLL cells, and confirmed using CD38 transfectants of the originally CD49d(+)CD38(-) CLL-derived cell line Mec-1. Results indicate that CD49d(+)CD38(+) cells adhered more efficiently onto CD49d-specific substrates than CD49d(+)CD38(-) cells (P < 0.001). Upon adhesion, CD49d(+)CD38(+) cells underwent distinctive changes in cell shape and morphology, with higher levels of phosphorylated Vav-1 than CD49d(+)CD38(-) cells (P = 0.0006) and a more complex distribution of F-actin to the adhesion sites. Lastly, adherent CD49d(+)CD38(+) cells were more resistant to serum-deprivation-induced (P < 0.001) and spontaneous (P = 0.03) apoptosis than the CD49d(+)CD38(-) counterpart. Altogether, our results point to a direct role for CD38 in enhancing CD49d-mediated adhesion processes in CLL, thus providing an explanation for the negative clinical impact exerted by these molecules when coexpressed in neoplastic cells.
Pascale Louisplence - One of the best experts on this subject based on the ideXlab platform.
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nonclassical cd4 CD49b regulatory t cells as a better alternative to conventional cd4 cd25 t cells to dampen arthritis severity
Journal of Immunology, 2016Co-Authors: Rita Vicente, Julie Quentin, Delphine Martire, Annelaure Maussetbonnefont, Christian Jorgensen, Pascale Louisplence, Paul Chuchana, Mailys CrenAbstract:Promising immunotherapeutic strategies are emerging to restore tolerance in autoimmune diseases by triggering an increase in the number and/or the function of endogenous regulatory T (Treg) cells, which actively control pathological immune responses. Evidence suggests a remarkable heterogeneity in peripheral Treg cells that warrants their better characterization in terms of phenotype and suppressive function, to determine which subset may be optimally suitable for a given clinical situation. We found that repetitive injections of immature dendritic cells expanded Foxp3-negative CD49b(+) Treg cells that displayed an effector memory phenotype. These expanded Treg cells were isolated ex vivo for transcriptome analysis and found to contain multiple transcripts of the canonical Treg signature shared mainly by CD25(+) but also by other subphenotypes. We characterized the CD49b(+) Treg cell phenotype, underscoring its similarities with the CD25(+) Treg cell phenotype and highlighting some differential expression patterns for several markers, including lymphocyte activation gene 3, KLRG1, CD103, ICOS, CTLA-4, and granzyme B. Comparison of the CD25(+) and CD49b(+) Treg cells' suppressive mechanisms, in vitro and in vivo, revealed the latter's potent suppressive activity, which was partly dependent on IL-10 secretion. Altogether, our results strongly suggest that expression of several canonical Treg cell markers and suppressive function could be Foxp3 independent, and underscore the therapeutic potential of IL-10-secreting CD49b(+) Treg cells in arthritis.
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a8 26 inducible il 10 secreting CD49b treg cells as cell based therapy for rheumatoid arthritis
Annals of the Rheumatic Diseases, 2014Co-Authors: Julie Quentin, Rita Vicente, Delphine Martire, Annelaure Maussetbonnefont, Christian Jorgensen, Pascale LouisplenceAbstract:Background Adoptive transfer of regulatory T cells (Tregs) is a promising approach to restore tolerance in autoimmune diseases. However based on the heterogeneity of the Tregs, we need to precisely establish which Tregs will be able to dampen efficiently the immune response in the various settings. We previously showed the potential of CD49b + Treg cells to protect and prevent an experimental model of arthritis. Nevertheless the optimal injection dose, the phenotype and the in vivo -suppressive mechanism of these Treg cells remain unknown. In our study, we investigated and compared the therapeutic potential of CD25 + FoxP3 + and induced IL10-secreting CD49b + Treg cells in an experimental model of arthritis, the collagen-induced arthritis (CIA). Materials and Methods IL-10 secreting CD49b + Treg cells were generated in naive mice following repetitive injections of immature DCs (iDCs). Treg purification was based on the negative selection of CD4 T cells isolated from spleen and liver of the iDC-vaccinated mice. Cell sorting was performed to obtain 98% pure CD49b + or CD25 + Treg cells. Several doses of CD49b + were intravenously (i.v.) injected at day 28 in established CIA. Clinical signs of arthritis were scored, as well as biological parameters such as the level of anti-bCII antibodies in sera and the cytokine profile of bCII specific T cells. Phenotypes of both Treg cells were compared as well as their suppressive activity in vitro and in vivo. Results Several doses of CD49 + Treg cells were tested in curative settings experiments. The dose of 10 5 CD49b + or CD25 + cells reverse clinical symptoms of arthritis while interestingly, a lack of efficacy was observed after higher doses. In vitro suppressive experiments confirmed the similar efficiency of both populations and phenotype analyses of CD49b + Treg cells showed expression profile of several Treg specific markers (LAP + , LAG + , CTLA-4 high ). Moreover, in an OVA-specific model of inflammation, we demonstrated the high impact of the CD49b Treg cells on the proliferation of effector cells in vivo. Conclusions Altogether, our results confirm the therapeutic potential of IL-10 secreting T cells in experimental model of arthritis in curative settings and unravel their mechanism of suppression.
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adoptive transfer of il 10 secreting cd4 CD49b regulatory t cells suppresses ongoing arthritis
Journal of Autoimmunity, 2010Co-Authors: Louismarie Charbonnier, Julie Quentin, Christian Jorgensen, Wanda G H Han, Tom W J Huizinga, Jochen Zwerina, Rene E M Toes, Pascale LouisplenceAbstract:We have previously demonstrated, in the collagen-induced arthritis model (CIA), that repetitive injections of immature bone-marrow-derived dendritic cells (iDCs) induce the expansion of a population of CD4CD49b-expressing cells, and that their adoptive transfer results in protection against CIA in a prophylactic setting. However, the in vivo mechanism responsible for their expansion, as well as their therapeutic potential in established disease remains to be defined. In the present study, we show that expression of the MHC class II molecules on iDCs is required for their expansion thus identifying these cells as MHC class II-restricted T cells. Using adoptive transfer of Thy1.1 positive cells, it is shown that iDC-induced CD4(+)CD49b(+) T cells home to the lymph nodes draining the inflamed tissue. The high immunomodulatory potential of these cells was underscored following their adoptive transfer in a model of contact hypersensitivity. Finally, we assessed and compared the therapeutic potential of iDC-inducible CD4(+)CD49b(+) T cells with that of iDCs in established CIA. Repetitive injections of iDCs in arthritic mice failed to decrease the severity of established disease. In contrast however, a single injection of iDC-induced CD4(+)CD49b(+) T cells reversed clinical symptoms of arthritis and provided long-lasting protection. Together, our data indicate that iDC-induced CD4(+)CD49b(+) T cells are bona fide T regulatory cells with strong immunomodulatory properties that are not only able to prevent disease onset, but also to interfere with an ongoing inflammatory immune response.
Francesca Rossi - One of the best experts on this subject based on the ideXlab platform.
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CD49d is overexpressed by trisomy 12 chronic lymphocytic leukemia cells: evidence for a methylation-dependent regulation mechanism.
Blood, 2013Co-Authors: Antonella Zucchetto, Riccardo Bomben, Francesca Rossi, Dania Benedetti, Chiara Caldana, Erika Tissino, Michele Dal Bo, Evelyn Hutterer, Federico Pozzo, Giovanni D'arenaAbstract:CD49d is a negative prognosticator in chronic lymphocytic leukemia (CLL), expressed by ~40% of CLL cases, and associated with aggressive and accelerated clinical courses. In the present study, analyzing CD49d expression in a wide CLL cohort (n=1200) belonging to different cytogenetic groups, we report that trisomy 12 CLL almost universally expressed CD49d, and were characterized by the highest CD49d expression levels among all CD49d + CLL. Through bisulfite genomic sequencing, we demonstrated that while CD49d + /trisomy12 CLL almost completely lacked methylation of the CD49d gene, CD49d - /no trisomy12 CLL were overall methylated, the methylation levels being inversely correlated to CD49d expression (p=0.0001). Consistently, CD49d expression was recovered in CD49d - hypermethylated CLL cells upon in-vitro treatment with the hypomethylating agent 5-aza-29-deoxycytidine. These findings may contribute to explain the clinico-biological features of trisomy 12 CLL, including the high rates of cell proliferation and disease progression, lymph node involvement and predisposition to Richter9s syndrome transformation.
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CD49d Is Overexpressed in Trisomy 12 Chronic Lymphocytic Leukemia by an Epigenetic-Dependent Transcriptional Control
Blood, 2012Co-Authors: Antonella Zucchetto, Riccardo Bomben, Francesca Rossi, Davide Rossi, Dania Benedetti, Chiara Caldana, Erika Tissino, Michele Dal Bo, Francesco Zaja, Gabriele PozzatoAbstract:Abstract 929 CD49d is an adhesion molecule with a variable expression in chronic lymphocytic leukemia (CLL). Only one third of CLL display CD49d expression in a significant fraction of cells, the remaining cases either expressing very low levels or completely lacking its expression. The negative prognostic impact of CD49d in CLL and its key role in microenvironmental interactions have been broadly described by several studies, whereas information on the mechanisms regulating CD49d expression in CLL is still lacking. Aiming to understand the genetic mechanisms underlying the different expression pattern of CD49d in CLL, CD49d expression was investigated by flow cytometry in the neoplastic component of 972 CLL patients, and correlated with cytogenetic profiles assessed by fluorescence in situ hybridization (FISH). Using the 30% positive cut-off value, 603 cases (62%) were CD49d-, whereas 369 cases (38%) were CD49d+. Correlation of CD49d expression with the major cytogenetic alterations (del13q14.3, trisomy 12, del11q22-q23-, del17p13.1), highlighted a very strong association between CD49d expression and the presence of trisomy 12 (p 99% purity) CD49d- and CD49d+ components from 3 CLL cases characterized by both CD49d bimodal expression (27%, 57%, and 75% of CD49d positive cells), and the presence of trisomy 12 in a fraction of the cells (25%, 42% and 63% respectively). In all cases, the CD49d- components almost completely lacked trisomy 12 (5%, 4%, and 0%), whereas the CD49d+ fractions displayed 70%, 62%, and 75% of trisomy 12, respectively (p A gene expression profiling was performed comparing CD49d+/trisomy12 (n=5) versus CD49d-/normal FISH CLL (n=5). According to bioinformatics tools for global analysis of gene function, the “Chromatin modification” (p Altogether, our results demonstrate that the overall down-regulated CD49d expression characterizing CLL is subjected to epigenetic control. Re-expression of CD49d may occur through a fine regulation of methyltransferase and chromatin modification processes, particularly active in trisomy 12 CLL, where CD49d expression may have a role in determining the clinical and biological features of this particular CLL subset. Disclosures: No relevant conflicts of interest to declare.
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cd49d expression identifies a chronic lymphocytic leukemia cll subset with high levels of circulating cd34 cells co expressing endothelial cell markers
Blood, 2009Co-Authors: Francesca Rossi, Antonella Zucchetto, D Benedetti, Claudio Tripodo, Riccardo Bomben, Davide Rossi, Giovanni Del Poeta, Gabriele Pozzato, Gianluca Gaidano, Valter GatteiAbstract:Abstract 2329 Poster Board II-306 Introduction: In chronic lymphocytic leukemia (CLL), CD49d, often in association with CD38, has been shown to mark a disease subset with poor prognosis. Functionally, both molecules act as counter-receptors for surface structures (i.e. VCAM-1/CD106 and CD31) usually expressed by the endothelial/stromal component of tumor micro-environment. We have recently identified a micro-environmental circuitry which involves CD38 triggering, and eventually determines an enrichment of the VCAM-1/CD106-expressing endothelial component detected in the context of CLL infiltrates found in bone marrow biopsies. Data was also provided that CD49d/VCAM-1 interactions are active in delivering pro-survival signals to CD49d-expressing CLL cells (Zucchetto et al, Cancer Res, 69, 4001, 2009). In this study, we investigated the amount of circulating progenitors with endothelial phenotype in CLL samples with different CD49d and CD38 expression levels. Methods: Peripheral blood (PB) samples from 91 CLL cases purposely selected with WBC>25,000/μl (B cells absolute lymphocyte count >10,000/μl) were evaluated by multiparametric flow cytometry for the absolute count of circulating CD34 + cells (ISHAGE protocol in single platform). Whenever possible (i.e. if a cluster of at least 100 CD34 + cells was detectable), a further characterization was performed (4-6 colours flow cytometry) for circulating endothelial cells (CEC), identified as a CD34 + CD45 low cell population co-expressing one of the following endothelial markers: CD309/VEGFR-2, CD144/VE-cadherin, CD106/VCAM-1 and CD146/Muc-18. CD49d and CD38 expression by CLL cells was considered positive if exceeding the standard cut-off value of 30% of positive cells. Results: PB absolute CD34 + cell counts were 7.5±7.5/μl in CD49d + CLL (32 cases), vs. 3.3±2.7/μl in CD49d − CLL (59 cases; p=2.6×10 −4 ), or 9.4±8.7/μl in CD49d + CLL (30 cases) vs. 4.6±2.9/μl in CD49d − CLL (18 cases; p=0.004) when only cases phenotyped for CEC were considered. Furthermore, when samples were stratified also for CD38 expression, values of circulating CD34 + cells increased to 10.6±10.1/μl in CD38 + CD49d + CLL (11 cases) vs. 3.1±2.4/μl in CD38 − CD49d − (51cases; p=1×10 −5 ). Regarding the absolute quantification of CEC, a CD49d + phenotype again marked the CLL subset with the highest CEC count, as identified by the expression of either the CD309/VEGFR-2 (CEC counts 1.7±2.3/μl in CD49d + CLL vs. 0.5±0.5/μl CD49d − CLL; p=0.009) or the CD144/VE-cadherin (CEC counts 0.8±1/μl in CD49d + CLL vs. 0.3±0.5/μl in CD49d − CLL; p=0.057) endothelial markers on CD34 + CD45 low cells. Notably, CEC from CD49d + CLL expressed CD106/VCAM-1 in virtually all cells (1.6±2.4/μl), while the other marker of endothelial activation CD146/Muc-18 was detected in a fraction of CEC only (0.4±0.9/μl). Conclusions: CD49d and CD38 expression by CLL cells identify a disease subset with significantly higher number of both circulating CD34 + cells and CEC. This phenomenon could be explained considering several aspects: i) the sharing of common phenotypic markers between CLL cells and CD34 + progenitors, including CD38 and CD49d, which could be responsible for a displacement of CD34 + progenitors in the context of micro-environmental niches; ii) the known capacity of CLL cells, especially with a unmutated IGHV gene status and/or a CD38 + CD49d + phenotype to produce pro-angiogenic factors including Ang-2; iii) the rare PB cells expressing CD34 and CEC markers may represent CLL cell precursors with tumor-initiating cell features. Studies are currently ongoing to dissect among these hypotheses Disclosures: No relevant conflicts of interest to declare.
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cd38 cd31 the ccl3 and ccl4 chemokines and cd49d vascular cell adhesion molecule 1 are interchained by sequential events sustaining chronic lymphocytic leukemia cell survival
Cancer Research, 2009Co-Authors: Antonella Zucchetto, Debora Lorenzon, D Benedetti, Claudio Tripodo, Riccardo Bomben, Daniela Marconi, Fleur Bossi, Massimo Degan, Francesca Rossi, Davide RossiAbstract:CD38 and CD49d are associated negative prognosticators in chronic lymphocytic leukemia (CLL). Despite evidence that both molecules are involved in interactions occurring between CLL and normal cells in the context of CLL-involved tissues, a functional link is still missing. Using gene expression profiles comparing CD38(+)CD49d(+) versus CD38(-)CD49d(-) CLL cells, we showed overexpression of the CCL3 and CCL4 chemokines in cells from the former group. These chemokines were also up-regulated by CD38 signals in CLL; moreover, CCL3 was expressed by CLL cells from bone marrow biopsies (BMB) of CD38(+)CD49d(+) but not CD38(-)CD49d(-) cases. High levels of CCR1 and, to a lesser extent, CCR5, the receptors for CCL3 and CCL4, were found in CLL-derived monocyte-macrophages. Consistently, CCL3 increased monocyte migration, and CD68(+) macrophage infiltration was particularly high in BMB from CD38(+)CD49d(+) CLL. Conditioned media from CCL3-stimulated macrophages induced endothelial cells to express vascular cell adhesion molecule-1 (VCAM-1), the CD49d ligand, likely through tumor necrosis factor alpha overproduction. These effects were apparent in BMB from CD38(+)CD49d(+) CLL, where lymphoid infiltrates were characterized by a prominent meshwork of VCAM-1(+) stromal/endothelial cells. Lastly, CD49d engagement by VCAM-1 transfectants increased viability of CD38(+)CD49d(+) CLL cells. Altogether, CD38 and CD49d can be thought of as parts of a consecutive chain of events ultimately leading to improved survival of CLL cells.
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cd38 cd31 the ccl3 and ccl4 chemokines and cd49d vascular cell adhesion molecule 1 are interchained by sequential events sustaining chronic lymphocytic leukemia cell survival
Cancer Research, 2009Co-Authors: Antonella Zucchetto, Debora Lorenzon, D Benedetti, Claudio Tripodo, Riccardo Bomben, Daniela Marconi, Fleur Bossi, Massimo Degan, Michele Dal Bo, Francesca RossiAbstract:CD38 and CD49d are associated negative prognosticators in chronic lymphocytic leukemia (CLL). Despite evidence that both molecules are involved in interactions occurring between CLL and normal cells in the context of CLL-involved tissues, a functional link is still missing. Using gene expression profiles comparing CD38+CD49d+ versus CD38−CD49d− CLL cells, we showed overexpression of the CCL3 and CCL4 chemokines in cells from the former group. These chemokines were also up-regulated by CD38 signals in CLL; moreover, CCL3 was expressed by CLL cells from bone marrow biopsies (BMB) of CD38+CD49d+ but not CD38−CD49d− cases. High levels of CCR1 and, to a lesser extent, CCR5, the receptors for CCL3 and CCL4, were found in CLL-derived monocyte-macrophages. Consistently, CCL3 increased monocyte migration, and CD68+ macrophage infiltration was particularly high in BMB from CD38+CD49d+ CLL. Conditioned media from CCL3-stimulated macrophages induced endothelial cells to express vascular cell adhesion molecule-1 (VCAM-1), the CD49d ligand, likely through tumor necrosis factor α overproduction. These effects were apparent in BMB from CD38+CD49d+ CLL, where lymphoid infiltrates were characterized by a prominent meshwork of VCAM-1+ stromal/endothelial cells. Lastly, CD49d engagement by VCAM-1 transfectants increased viability of CD38+CD49d+ CLL cells. Altogether, CD38 and CD49d can be thought of as parts of a consecutive chain of events ultimately leading to improved survival of CLL cells. [Cancer Res 2009;69(9):4001–9]
Alessandra Ferrajoli - One of the best experts on this subject based on the ideXlab platform.
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morphological immunophenotypic and genetic features of chronic lymphocytic leukemia with trisomy 12 a comprehensive review
Haematologica, 2018Co-Authors: Francesco Autore, Paolo Strati, Luca Laurenti, Alessandra FerrajoliAbstract:Chronic lymphocytic leukemia is an extremely heterogeneous disease and prognostic factors such as chromosomal abnormalities are important predictors of time to first treatment and survival. Trisomy 12 is the second most frequent aberration detected by fluorescence in situ hybridization at the time of diagnosis (10–25%), and it confers an intermediate prognostic risk, with a median time to first treatment of 33 months and a median overall survival of 114 months. Here, we review the unique morphological, immunophenotypic, and genetic characteristics of patients with chronic lymphocytic leukemia and trisomy 12. These patients carry a significantly higher expression of CD19, CD22, CD20, CD79b, CD24, CD27, CD38, CD49d, sIgM, sIgk, and sIgλ and lower expression of CD43 compared with patients with normal karyotype. Circulating cells show increased expression of the integrins CD11b, CD18, CD29, and ITGB7, and of the adhesion molecule CD323. Patients with chronic lymphocytic leukemia and trisomy 12 frequently have unmutated IGHV, ZAP-70 positivity, and closely homologous stereotyped B-cell receptors. They rarely show TP53 mutations but frequently have NOTCH1 mutations, which can be identified in up to 40% of those with a rapidly progressive clinical course.
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cd49d is the strongest flow cytometry based predictor of overall survival in chronic lymphocytic leukemia
Journal of Clinical Oncology, 2014Co-Authors: Pietro Ulia, Antonella Zucchetto, Tai D Shanafel, Christophe Fega, Lilla Cro, Holge Nuckel, Luca Aldini, Antonina V Kurtova, Alessandra Ferrajoli, Ja A UrgeAbstract:Purpose Although CD49d is an unfavorable prognostic marker in chronic lymphocytic leukemia (CLL), definitive validation evidence is lacking. A worldwide multicenter analysis was performed using published and unpublished CLL series to evaluate the impact of CD49d as an overall (OS) and treatment-free survival (TFS) predictor. Patients and Methods A training/validation strategy was chosen to find the optimal CD49d cutoff. The hazard ratio (HR) for death and treatment imposed by CD49d was estimated by pooled analysis of 2,972 CLLs; Cox analysis stratified by center and stage was used to adjust for confounding variables. The importance of CD49d over other flow cytometry–based prognosticators (eg, CD38, ZAP-70) was ranked by recursive partitioning. Results Patients with ≥ 30% of neoplastic cells expressing CD49d were considered CD49d+. Decrease in OS at 5 and 10 years among CD49d+ patients was 7% and 23% (decrease in TFS, 26% and 25%, respectively). Pooled HR of CD49d for OS was 2.5 (2.3 for TFS) in univariate...
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cd49d is the strongest flow cytometry based predictor of overall survival in chronic lymphocytic leukemia
Blood, 2013Co-Authors: Pietro Ulia, Antonella Zucchetto, Tai D Shanafel, Christophe Fega, Lilla Cro, Holge Nuckel, Luca Aldini, Antonina V Kurtova, Alessandra Ferrajoli, Ja A UrgeAbstract:![Graphic][1] Purpose Although CD49d is an unfavorable prognostic marker in chronic lymphocytic leukemia (CLL), definitive validation evidence is lacking. A worldwide multi-center analysis was performed using published and unpublished CLL series to evaluate the impact of CD49d as overall survival (OS) and treatment free survival (TFS) predictor. Patients and Methods A training/validation strategy was chosen to find the optimal CD49d cut-off. The hazard ratio (HR) for death and treatment imposed by CD49d was estimated by pooled analysis of 2,972 CLL, and Cox analysis stratified by center and stage was used to adjust for confounding variables. The importance of CD49d over other flow cytometry-based prognosticators (CD38, ZAP-70) was ranked by recursive partitioning. Results Patients with ≥30% of neoplastic cells expressing CD49d were considered CD49d+. The decrease in OS at 5 and 10-years among CD49d+ cases was 7% and 23% (decrease in TFS 26% and 25% respectively). The pooled HR of CD49d for OS was 2.5 (2.3 for TFS) in univariate analysis. This HR remained significant and of similar magnitude (HR=2.0) in a Cox model adjusted for clinical and biological prognosticators. Hierarchical trees including all cases, or restricted to early stage or patients ≤65 years, always selected CD49d as the most important flow-cytometry-based biomarker, with negligible additional prognostic information added by CD38 or ZAP-70. Consistently, by bivariate analysis, CD49d reliably identified patients' subsets with poorer outcome independent of CD38 and ZAP-70. Conclusions In this analysis of ∼3000 patients, CD49d emerged as the strongest flow cytometry-based predictor of OS and TFS in CLL. Disclosures: Shanafelt: Genentech: Research Funding; Glaxo-Smith-Kline: Research Funding; Cephalon: Research Funding; Hospira: Research Funding; Celgene: Research Funding; Polyphenon E International: Research Funding. Burger: Pharmacyclics: Research Funding. [1]: /embed/inline-graphic-2.gif
Max Lohning - One of the best experts on this subject based on the ideXlab platform.
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b cells negatively regulate the establishment of CD49b t bet resting memory t helper cells in the bone marrow
Frontiers in Immunology, 2016Co-Authors: Shintaro Hojyo, Asami Hanazawa, Jana Sarkander, Christian Manne, Mathias Mursell, David Zimmel, Jinfang Zhu, William E Paul, Simon Fillatreau, Max LohningAbstract:During an immune reaction, some antigen-experienced CD4 T cells relocate from secondary lymphoid organs (SLOs) to the bone marrow (BM) in a CD49b-dependent manner and reside and rest there as professional memory CD4 T cells. However, it remains unclear how the precursors of BM memory CD4 T cells are generated in the SLOs. While several studies have so far shown that B cell depletion reduces the persistence of memory CD4 T cells in the spleen, we here show that B cell depletion enhances the establishment of memory CD4 T cells in the BM and that B cell transfer conversely suppresses it. Interestingly, the number of antigen-experienced CD4 T cells in the BM synchronizes the number of CD49b+T-bet+ antigen-experienced CD4 T cells in the spleen. CD49b+T-bet+ antigen-experienced CD4 T cells preferentially localize in the red pulp area of the spleen and the BM in a T-bet-independent manner. We suggest that B cells negatively control the generation of CD49b+T-bet+ precursors of resting memory CD4 T cells in the spleen and may play a role in bifurcation of activated effector and resting memory CD4 T cell lineages.
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CD49b dependent establishment of t helper cell memory
Immunology and Cell Biology, 2013Co-Authors: Asami Hanazawa, Koji Hayashizaki, Kenta Shinoda, Hideo Yagita, Ko Okumura, Max Lohning, Takahiro Hara, Shizue Taniichi, Koichi Ikuta, Beate EckesAbstract:CD4 T cells play a key role in immunological memory. We have demonstrated that professional memory CD4 T cells reside and rest in the bone marrow (BM). However, the molecular mechanisms of their establishment in the BM and their maintenance remain unclear. We here show that memory CD4 T cells express high levels of CD49b and that CD49b-deficient or -blocked memory CD4 T-cell precursors fail to migrate from blood into the marrow of the bone, and they especially fail to transmigrate through sinusoidal endothelial cells of the BM. In the marrow, memory CD4 T cells and the precursors contact stromal cells expressing collagen II that are specific ligands for CD49b. Interestingly, memory CD4 T cells on day 117 of an immune response also dock on IL-7(+)/collagen XI(+) stromal cells, whereas memory precursors on day 12 do not. These results indicate that the collagen receptor CD49b is required for the migration of memory CD4 T-cell precursors into their survival niches of the bone marrow.
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CD49b cd69 dependent generation of resting t helper cell memory
Frontiers in Immunology, 2013Co-Authors: Asami Hanazawa, Max Lohning, Andreas Radbruch, Koji TokoyodaAbstract:In the absence of antigen, memory T helper (Th) cells are maintained in a resting state. Recently it has been shown that bone marrow (BM) is a major reservoir of resting memory Th cells. In a given immune response, less than 10% of the activated CD4 T cells are recruited to the pool of resting BM memory Th cells. Here we review recent evidence that CD69 and CD49b control homing of memory Th cell precursors to the BM. During the effector phase of an immune response, about 10% of activated CD4 T cells in the spleen express both CD69 and CD49b, and thus qualify as precursors of resting memory Th cells of BM. Loss or blockade of CD69 and CD49b expression on CD4 T cells impairs the generation of resting memory Th cells in the BM. Moreover, in the absence of BM memory Th cells in CD69-deficient mice, T-cell help for B cells is impaired, confirming the central role of BM memory Th cells in the maintenance of immunological memory.