The Experts below are selected from a list of 60 Experts worldwide ranked by ideXlab platform
Susan Chan - One of the best experts on this subject based on the ideXlab platform.
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biclonal and biallelic deletions occur in 20 of b all cases with ikzf1 mutations
Leukemia, 2013Co-Authors: Arnaud Dupuis, Marie-pierre Gaub, Michèle Legrain, Bernard Drenou, Laurent Mauvieux, Raoul Herbrecht, Susan Chan, P Lutz, Philippe KastnerAbstract:The IKZF1 gene encodes the Ikaros Transcription Factor, a key regulator of lymphocyte differentiation.1 IKZF1 is mutated in 20–30% of B-cell acute lymphoblastic leukemia (B-ALL) mostly by genomic deletions.2, 3, 4 Several reports have shown that IKZF1 deletions are associated with an adverse prognosis, especially in pediatric patients.3, 4, 5, 6, 7, 8, 9, 10 Ikaros mutations fall mainly into three types: (a) deletions of exons 4–7 (Δ4–7), which lead to the synthesis of the Ikaros-6 (Ik6) dominant-negative isoform; (b) deletions of exons 2–7 (Δ2–7), which delete the initiation codon and lead to haploinsufficiency; and (c) larger deletions of various sizes, which affect the coding exons (referred to below as ‘complete’ deletions). Thus, IKZF1 mutations have until now been separated into dominant-negative and haploinsufficient groups. Here we report that about 20% of B-ALL patients with IKZF1 mutations present two distinct deletions. These deletions are biallelic, leading to a complete loss of Ikaros function, or biclonal, marking distinct clones within the leukemia. These results highlight a more complex picture of IKZF1 loss of function in B-ALL than thought previously.
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Ikaros controls isotype selection during immunoglobulin class switch recombination.
Journal of Experimental Medicine, 2009Co-Authors: Maclean Sellars, Bernardo Reina-san-martin, Philippe Kastner, Susan ChanAbstract:Class switch recombination (CSR) allows the humoral immune response to exploit different effector pathways through specific secondary antibody isotypes. However, the molecular mechanisms and Factors that control immunoglobulin (Ig) isotype choice for CSR are unclear. We report that deficiency for the Ikaros Transcription Factor results in increased and ectopic CSR to IgG(2b) and IgG(2a), and reduced CSR to all other isotypes, regardless of stimulation. Ikaros suppresses active chromatin marks, Transcription, and activation-induced cytidine deaminase (AID) accessibility at the gamma2b and gamma2a genes to inhibit class switching to these isotypes. Further, Ikaros directly regulates isotype gene Transcription as it directly binds the Igh 3' enhancer and interacts with isotype gene promoters. Finally, Ikaros-mediated repression of gamma2b and gamma2a Transcription promotes switching to other isotype genes by allowing them to compete for AID-mediated recombination at the single-cell level. Thus, our results reveal Transcriptional competition between constant region genes in individual cells to be a critical and general mechanism for isotype specification during CSR. We show that Ikaros is a master regulator of this competition.
Maclean Sellars - One of the best experts on this subject based on the ideXlab platform.
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Ikaros controls isotype selection during immunoglobulin class switch recombination.
Journal of Experimental Medicine, 2009Co-Authors: Maclean Sellars, Bernardo Reina-san-martin, Philippe Kastner, Susan ChanAbstract:Class switch recombination (CSR) allows the humoral immune response to exploit different effector pathways through specific secondary antibody isotypes. However, the molecular mechanisms and Factors that control immunoglobulin (Ig) isotype choice for CSR are unclear. We report that deficiency for the Ikaros Transcription Factor results in increased and ectopic CSR to IgG(2b) and IgG(2a), and reduced CSR to all other isotypes, regardless of stimulation. Ikaros suppresses active chromatin marks, Transcription, and activation-induced cytidine deaminase (AID) accessibility at the gamma2b and gamma2a genes to inhibit class switching to these isotypes. Further, Ikaros directly regulates isotype gene Transcription as it directly binds the Igh 3' enhancer and interacts with isotype gene promoters. Finally, Ikaros-mediated repression of gamma2b and gamma2a Transcription promotes switching to other isotype genes by allowing them to compete for AID-mediated recombination at the single-cell level. Thus, our results reveal Transcriptional competition between constant region genes in individual cells to be a critical and general mechanism for isotype specification during CSR. We show that Ikaros is a master regulator of this competition.
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the role of the Ikaros Transcription Factor in b cell development activation and immunoglobulin class switch recombination
2008Co-Authors: Maclean SellarsAbstract:Le facteur de Transcription, Ikaros, est crucial au lineage B. Nous avons etudie comment Ikaros regule le developpement, l’activation et la commutation isotypique des cellules B. Premierement, nous avons montre qu’Ikaros contribue a la differenciation des cellules B en induisant l’expression du recepteur de l'Interleukine 7 dans les cellules pro-B. Puis, nous avons revele qu'Ikaros regule la proliferation des cellules B en controlant l'activation des proteines kinases ERK et p38 apres stimulation du recepteur des cellules B. Ces donnees suggerent qu'Ikaros joue un role central dans la signalisation du recepteur des cellules B. Enfin, nous avons montre qu’Ikaros reprime la commutation de classe vers les isotypes IgG2b et IgG2a et induit la commutation vers tous les autres isotypes. De plus, Ikaros controle la commutation de classe et specifie le choix des isotypes par un mecanisme de competition Transcriptionelle entre les genes codants pour les regions constantes des immunoglobulines.
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Notch activation is an early and critical event during T-Cell leukemogenesis in Ikaros-deficient mice.
Molecular and Cellular Biology, 2006Co-Authors: Alexis Dumortier, Maclean Sellars, Robin Jeannet, Peggy Kirstetter, Eva Kleinmann, Nuno R Dos Santos, Christelle Thibault, Jochen Barths, Jacques Ghysdael, Jennifer A PuntAbstract:The Ikaros Transcription Factor is both a key regulator of lymphocyte differentiation and a tumor suppressor in T lymphocytes. Mice carrying a hypomorphic mutation (Ik(L/L)) in the Ikaros gene all develop thymic lymphomas. Ik(L/L) tumors always exhibit strong activation of the Notch pathway, which is required for tumor cell proliferation in vitro. Notch activation occurs early in tumorigenesis and may precede transformation, as ectopic expression of the Notch targets Hes-1 and Deltex-1 is detected in thymocytes from young Ik(L/L) mice with no overt signs of transformation. Notch activation is further amplified by secondary mutations that lead to C-terminal truncations of Notch 1. Strikingly, restoration of Ikaros activity in tumor cells leads to a rapid and specific downregulation of Notch target gene expression and proliferation arrest. Furthermore, Ikaros binds to the Notch-responsive element in the Hes-1 promoter and represses Notch-dependent Transcription from this promoter. Thus, Ikaros-mediated repression of Notch target gene expression may play a critical role in defining the tumor suppressor function of this Factor.
Ethan M Shevach - One of the best experts on this subject based on the ideXlab platform.
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expression of helios an Ikaros Transcription Factor family member differentiates thymic derived from peripherally induced foxp3 t regulatory cells
Journal of Immunology, 2010Co-Authors: Angela M Thornton, Patricia E Korty, Dat Q Tran, Elizabeth A Wohlfert, Patrick E Murray, Yasmine Belkaid, Ethan M ShevachAbstract:Helios, a member of the Ikaros Transcription Factor family, is preferentially expressed at the mRNA level by regulatory T cells (Treg cells). We evaluated Helios protein expression using a newly generated mAb and demonstrated that it is expressed in all thymocytes at the double negative 2 stage of thymic development. Although Helios was expressed by 100% of CD4(+)CD8(-)Foxp3(+) thymocytes, its expression in peripheral lymphoid tissues was restricted to a subpopulation ( approximately 70%) of Foxp3(+) T cells in mice and humans. Neither mouse nor human naive T cells induced to express Foxp3 in vitro by TCR stimulation in the presence of TGF-beta expressed Helios. Ag-specific Foxp3(+) T cells induced in vivo by Ag feeding also failed to express Helios. Collectively, these results demonstrate that Helios is potentially a specific marker of thymic-derived Treg cells and raises the possibility that a significant percentage of Foxp3(+) Treg cells are generated extrathymically.
Philippe Kastner - One of the best experts on this subject based on the ideXlab platform.
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biclonal and biallelic deletions occur in 20 of b all cases with ikzf1 mutations
Leukemia, 2013Co-Authors: Arnaud Dupuis, Marie-pierre Gaub, Michèle Legrain, Bernard Drenou, Laurent Mauvieux, Raoul Herbrecht, Susan Chan, P Lutz, Philippe KastnerAbstract:The IKZF1 gene encodes the Ikaros Transcription Factor, a key regulator of lymphocyte differentiation.1 IKZF1 is mutated in 20–30% of B-cell acute lymphoblastic leukemia (B-ALL) mostly by genomic deletions.2, 3, 4 Several reports have shown that IKZF1 deletions are associated with an adverse prognosis, especially in pediatric patients.3, 4, 5, 6, 7, 8, 9, 10 Ikaros mutations fall mainly into three types: (a) deletions of exons 4–7 (Δ4–7), which lead to the synthesis of the Ikaros-6 (Ik6) dominant-negative isoform; (b) deletions of exons 2–7 (Δ2–7), which delete the initiation codon and lead to haploinsufficiency; and (c) larger deletions of various sizes, which affect the coding exons (referred to below as ‘complete’ deletions). Thus, IKZF1 mutations have until now been separated into dominant-negative and haploinsufficient groups. Here we report that about 20% of B-ALL patients with IKZF1 mutations present two distinct deletions. These deletions are biallelic, leading to a complete loss of Ikaros function, or biclonal, marking distinct clones within the leukemia. These results highlight a more complex picture of IKZF1 loss of function in B-ALL than thought previously.
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Ikaros controls isotype selection during immunoglobulin class switch recombination.
Journal of Experimental Medicine, 2009Co-Authors: Maclean Sellars, Bernardo Reina-san-martin, Philippe Kastner, Susan ChanAbstract:Class switch recombination (CSR) allows the humoral immune response to exploit different effector pathways through specific secondary antibody isotypes. However, the molecular mechanisms and Factors that control immunoglobulin (Ig) isotype choice for CSR are unclear. We report that deficiency for the Ikaros Transcription Factor results in increased and ectopic CSR to IgG(2b) and IgG(2a), and reduced CSR to all other isotypes, regardless of stimulation. Ikaros suppresses active chromatin marks, Transcription, and activation-induced cytidine deaminase (AID) accessibility at the gamma2b and gamma2a genes to inhibit class switching to these isotypes. Further, Ikaros directly regulates isotype gene Transcription as it directly binds the Igh 3' enhancer and interacts with isotype gene promoters. Finally, Ikaros-mediated repression of gamma2b and gamma2a Transcription promotes switching to other isotype genes by allowing them to compete for AID-mediated recombination at the single-cell level. Thus, our results reveal Transcriptional competition between constant region genes in individual cells to be a critical and general mechanism for isotype specification during CSR. We show that Ikaros is a master regulator of this competition.
David C Wraith - One of the best experts on this subject based on the ideXlab platform.
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comment on expression of helios an Ikaros Transcription Factor family member differentiates thymic derived from peripherally induced foxp3 t regulatory cells
Journal of Immunology, 2010Co-Authors: Johan Verhagen, David C WraithAbstract:Thornton et al. ([1][1]) reported recently that in both mouse and man, ∼70% of peripheral Foxp3+ regulatory T cells (Tregs) express the Transcription Factor Helios. Interestingly, they found that Foxp3+ cells generated in the thymus all coexpressed Helios, whereas Tregs generated in vitro from
