9 results on '"Al-Maarri M"'
Search Results
2. Aberrant splicing of the tumor suppressor CYLD promotes the development of chronic lymphocytic leukemia via sustained NF-kappaB signaling
- Author
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Hahn, M., Burckert, J.-P., Luttenberger, C. A., Klebow, S., Hess, M., Al-Maarri, M., Vogt, M., Reissig, S., Hallek, M., Wienecke-Baldacchino, Anke, Buch, T., Muller, Claire, Pallasch, C. P., Wunderlich, F. T., Waisman, A., and Hovelmeyer, N.
- Subjects
immune system diseases ,hemic and lymphatic diseases ,Genetics & genetic processes [F10] [Life sciences] ,Génétique & processus génétiques [F10] [Sciences du vivant] - Abstract
The pathogenesis of chronic lymphocytic leukemia (CLL) has been linked to constitutive NF-kappaB activation but the underlying mechanisms are poorly understood. Here we show that alternative splicing of the negative regulator of NF-kappaB and tumor suppressor gene CYLD regulates the pool of CD5(+) B cells through sustained canonical NF-kappaB signaling. Reinforced canonical NF-kappaB activity leads to the development of B1 cell-associated tumor formation in aging mice by promoting survival and proliferation of CD5(+) B cells, highly reminiscent of human B-CLL. We show that a substantial number of CLL patient samples express sCYLD, strongly implicating a role for it in human B-CLL. We propose that our new CLL-like mouse model represents an appropriate tool for studying ubiquitination-driven canonical NF-kappaB activation in CLL. Thus, inhibition of alternative splicing of this negative regulator is essential for preventing NF-kappaB-driven clonal CD5(+) B-cell expansion and ultimately CLL-like disease.
- Published
- 2017
3. Aberrant splicing of the tumor suppressor CYLD promotes the development of chronic lymphocytic leukemia via sustained NF-κB signaling
- Author
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Hahn, M, primary, Bürckert, J-P, additional, Luttenberger, C A, additional, Klebow, S, additional, Hess, M, additional, Al-Maarri, M, additional, Vogt, M, additional, Reißig, S, additional, Hallek, M, additional, Wienecke-Baldacchino, A, additional, Buch, T, additional, Muller, C P, additional, Pallasch, C P, additional, Wunderlich, F T, additional, Waisman, A, additional, and Hövelmeyer, N, additional
- Published
- 2017
- Full Text
- View/download PDF
4. AKT activity orchestrates marginal zone B cell development in mice and humans.
- Author
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Cox EM, El-Behi M, Ries S, Vogt JF, Kohlhaas V, Michna T, Manfroi B, Al-Maarri M, Wanke F, Tirosh B, Pondarre C, Lezeau H, Yogev N, Mittenzwei R, Descatoire M, Weller S, Weill JC, Reynaud CA, Boudinot P, Jouneau L, Tenzer S, Distler U, Rensing-Ehl A, König C, Staniek J, Rizzi M, Magérus A, Rieux-Laucat F, Wunderlich FT, Hövelmeyer N, and Fillatreau S
- Subjects
- Humans, Mice, Animals, Lymphoid Tissue, Signal Transduction, Spleen, Proto-Oncogene Proteins c-akt, B-Lymphocytes
- Abstract
The signals controlling marginal zone (MZ) and follicular (FO) B cell development remain incompletely understood. Here, we show that AKT orchestrates MZ B cell formation in mice and humans. Genetic models that increase AKT signaling in B cells or abolish its impact on FoxO transcription factors highlight the AKT-FoxO axis as an on-off switch for MZ B cell formation in mice. In humans, splenic immunoglobulin (Ig) D
+ CD27+ B cells, proposed as an MZ B cell equivalent, display higher AKT signaling than naive IgD+ CD27- and memory IgD- CD27+ B cells and develop in an AKT-dependent manner from their precursors in vitro, underlining the conservation of this developmental pathway. Consistently, CD148 is identified as a receptor indicative of the level of AKT signaling in B cells, expressed at a higher level in MZ B cells than FO B cells in mice as well as humans., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023. Published by Elsevier Inc.)- Published
- 2023
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5. Active Akt signaling triggers CLL toward Richter transformation via overactivation of Notch1.
- Author
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Kohlhaas V, Blakemore SJ, Al-Maarri M, Nickel N, Pal M, Roth A, Hövelmeyer N, Schäfer SC, Knittel G, Lohneis P, Nikolic M, Wiederstein JL, Franitza M, Georgomonolis T, Reinart N, Herling M, Herling C, Hartmann EM, Rosenwald A, Klapper W, Büttner R, Moia R, Rossi D, Boldorini R, Gaidano G, Frenzel LP, Reinhardt HC, Brüning JC, Hallek M, Krüger M, Peifer M, Pallasch CP, and Wunderlich FT
- Subjects
- Animals, Clonal Evolution, Disease Progression, Enzyme Activation, Gene Expression Regulation, Neoplastic, Genes, p53, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Leukemia, Lymphocytic, Chronic, B-Cell physiopathology, Lymphocytes, Tumor-Infiltrating immunology, Lymphoma, Large B-Cell, Diffuse genetics, Lymphoma, Large B-Cell, Diffuse physiopathology, Mice, Mice, Inbred C57BL, Phenotype, Phosphoproteins physiology, Proto-Oncogene Proteins c-akt genetics, Receptors, Antigen, B-Cell immunology, Signal Transduction physiology, Transcriptome, Tumor Microenvironment, Tumor Suppressor Protein p53 physiology, Up-Regulation, Leukemia, Lymphocytic, Chronic, B-Cell pathology, Lymphoma, Large B-Cell, Diffuse pathology, Neoplasm Proteins physiology, Proto-Oncogene Proteins c-akt physiology, Receptor, Notch1 physiology
- Abstract
Richter's transformation (RT) is an aggressive lymphoma that occurs upon progression from chronic lymphocytic leukemia (CLL). Transformation has been associated with genetic aberrations in the CLL phase involving TP53, CDKN2A, MYC, and NOTCH1; however, a significant proportion of RT cases lack CLL phase-associated events. Here, we report that high levels of AKT phosphorylation occur both in high-risk CLL patients harboring TP53 and NOTCH1 mutations as well as in patients with RT. Genetic overactivation of Akt in the murine Eµ-TCL1 CLL mouse model resulted in CLL transformation to RT with significantly reduced survival and an aggressive lymphoma phenotype. In the absence of recurrent mutations, we identified a profile of genomic aberrations intermediate between CLL and diffuse large B-cell lymphoma. Multiomics assessment by phosphoproteomic/proteomic and single-cell transcriptomic profiles of this Akt-induced murine RT revealed an S100 protein-defined subcluster of highly aggressive lymphoma cells that developed from CLL cells, through activation of Notch via Notch ligand expressed by T cells. Constitutively active Notch1 similarly induced RT of murine CLL. We identify Akt activation as an initiator of CLL transformation toward aggressive lymphoma by inducing Notch signaling between RT cells and microenvironmental T cells., (© 2021 by The American Society of Hematology.)
- Published
- 2021
- Full Text
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6. Activated gp130 signaling selectively targets B cell differentiation to induce mature lymphoma and plasmacytoma.
- Author
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Scherger AK, Al-Maarri M, Maurer HC, Schick M, Maurer S, Öllinger R, Gonzalez-Menendez I, Martella M, Thaler M, Pechloff K, Steiger K, Sander S, Ruland J, Rad R, Quintanilla-Martinez L, Wunderlich FT, Rose-John S, and Keller U
- Subjects
- Animals, Carcinogenesis genetics, Carcinogenesis immunology, Cell Differentiation genetics, Cytokine Receptor gp130 genetics, Disease Models, Animal, Female, Humans, Janus Kinases metabolism, Lymphocyte Activation genetics, Lymphoma genetics, Lymphoma pathology, Male, Mice, Plasmacytoma genetics, Plasmacytoma pathology, Proto-Oncogene Proteins c-myc genetics, Proto-Oncogene Proteins c-myc metabolism, STAT3 Transcription Factor metabolism, B-Lymphocytes immunology, Cell Differentiation immunology, Cytokine Receptor gp130 metabolism, Lymphoma immunology, Plasmacytoma immunology, Signal Transduction immunology
- Abstract
Aberrant activity of the glycoprotein 130 130/JAK/STAT3 (gp130/JAK/STAT3) signaling axis is a recurrent event in inflammation and cancer. In particular, it is associated with a wide range of hematological malignancies, including multiple myeloma and leukemia. Novel targeted therapies have only been successful for some subtypes of these malignancies, underlining the need for developing robust mouse models to better dissect the role of this pathway in specific tumorigenic processes. Here, we investigated the role of selective gp130/JAK/STAT3 activation by generating a conditional mouse model. This model targeted constitutively active, cell-autonomous gp130 activity to B cells, as well as to the entire hematopoietic system. We found that regardless of the timing of activation in B cells, constitutively active gp130 signaling resulted in the formation specifically of mature B cell lymphomas and plasma cell disorders with full penetrance, only with different latencies, where infiltrating CD138+ cells were a dominant feature in every tumor. Furthermore, constitutively active gp130 signaling in all adult hematopoietic cells also led to the development specifically of largely mature, aggressive B cell cancers, again with a high penetrance of CD138+ tumors. Importantly, gp130 activity abrogated the differentiation block induced by a B cell-targeted Myc transgene and resulted in a complete penetrance of the gp130-associated, CD138+, mature B cell lymphoma phenotype. Thus, gp130 signaling selectively provides a strong growth and differentiation advantage for mature B cells and directs lymphomagenesis specifically toward terminally differentiated B cell cancers.
- Published
- 2019
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7. Two mouse models reveal an actionable PARP1 dependence in aggressive chronic lymphocytic leukemia.
- Author
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Knittel G, Rehkämper T, Korovkina D, Liedgens P, Fritz C, Torgovnick A, Al-Baldawi Y, Al-Maarri M, Cun Y, Fedorchenko O, Riabinska A, Beleggia F, Nguyen PH, Wunderlich FT, Ortmann M, Montesinos-Rongen M, Tausch E, Stilgenbauer S, P Frenzel L, Herling M, Herling C, Bahlo J, Hallek M, Peifer M, Buettner R, Persigehl T, and Reinhardt HC
- Subjects
- Animals, Ataxia Telangiectasia Mutated Proteins genetics, Chromosome Deletion, Chromosomes, Human, Pair 11 genetics, Chromosomes, Human, Pair 17 genetics, Cyclophosphamide pharmacology, Gene Expression Profiling methods, Humans, Immunoblotting, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Mice, Inbred C57BL, Mice, Knockout, Poly (ADP-Ribose) Polymerase-1 antagonists & inhibitors, Poly(ADP-ribose) Polymerase Inhibitors pharmacology, Survival Analysis, Tumor Suppressor Protein p53 genetics, Ataxia Telangiectasia Mutated Proteins metabolism, Disease Models, Animal, Leukemia, Lymphocytic, Chronic, B-Cell metabolism, Poly (ADP-Ribose) Polymerase-1 metabolism, Tumor Suppressor Protein p53 metabolism
- Abstract
Chronic lymphocytic leukemia (CLL) remains an incurable disease. Two recurrent cytogenetic aberrations, namely del(17p), affecting TP53, and del(11q), affecting ATM, are associated with resistance against genotoxic chemotherapy (del17p) and poor outcome (del11q and del17p). Both del(17p) and del(11q) are also associated with inferior outcome to the novel targeted agents, such as the BTK inhibitor ibrutinib. Thus, even in the era of targeted therapies, CLL with alterations in the ATM/p53 pathway remains a clinical challenge. Here we generated two mouse models of Atm- and Trp53-deficient CLL. These animals display a significantly earlier disease onset and reduced overall survival, compared to controls. We employed these models in conjunction with transcriptome analyses following cyclophosphamide treatment to reveal that Atm deficiency is associated with an exquisite and genotype-specific sensitivity against PARP inhibition. Thus, we generate two aggressive CLL models and provide a preclinical rational for the use of PARP inhibitors in ATM-affected human CLL.ATM and TP53 mutations are associated with poor prognosis in chronic lymphocytic leukaemia (CLL). Here the authors generate mouse models of Tp53- and Atm-defective CLL mimicking the high-risk form of human disease and show that Atm-deficient CLL is sensitive to PARP1 inhibition.
- Published
- 2017
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8. Temporal and tissue-specific requirements for T-lymphocyte IL-6 signalling in obesity-associated inflammation and insulin resistance.
- Author
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Xu E, Pereira MMA, Karakasilioti I, Theurich S, Al-Maarri M, Rappl G, Waisman A, Wunderlich FT, and Brüning JC
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- Animals, Blood Glucose metabolism, Diet, High-Fat, Homeostasis, Interleukin-6 genetics, Lipid Metabolism, Male, Mice, Mice, Knockout, Receptors, Interleukin-6 genetics, Time Factors, Inflammation metabolism, Insulin Resistance, Interleukin-6 metabolism, Obesity metabolism, Signal Transduction, T-Lymphocytes metabolism
- Abstract
Low-grade inflammation links obesity to insulin resistance through the activation of tissue-infiltrating immune cells. Interleukin-6 (IL-6) is a crucial regulator of T cells and is increased in obesity. Here we report that classical IL-6 signalling in T cells promotes inflammation and insulin resistance during the first 8 weeks on a high-fat diet (HFD), but becomes dispensable at later stages (after 16 weeks). Mice with T cell-specific deficiency of IL-6 receptor-α (IL-6Rα
T-KO ) exposed to a HFD display improved glucose tolerance, insulin sensitivity and inflammation in liver and EWAT after 8 weeks. However, after 16 weeks, insulin resistance in IL-6RαT-KO epididymal white adipose tissue (EWAT) is comparable to that of controls, whereas the inflammatory profile is significantly worse. This coincided with a shift from classical T cell IL-6 signalling at 8 weeks, to enhanced IL-6 trans-signalling at 16 weeks. Collectively, our studies reveal that IL-6 action in T cells through classical IL-6 signalling promotes inflammation and insulin resistance early during obesity development, which can be compensated for by enhanced IL-6 trans-signalling at later stages.- Published
- 2017
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9. B-cell-specific conditional expression of Myd88p.L252P leads to the development of diffuse large B-cell lymphoma in mice.
- Author
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Knittel G, Liedgens P, Korovkina D, Seeger JM, Al-Baldawi Y, Al-Maarri M, Fritz C, Vlantis K, Bezhanova S, Scheel AH, Wolz OO, Reimann M, Möller P, López C, Schlesner M, Lohneis P, Weber AN, Trümper L, Staudt LM, Ortmann M, Pasparakis M, Siebert R, Schmitt CA, Klatt AR, Wunderlich FT, Schäfer SC, Persigehl T, Montesinos-Rongen M, Odenthal M, Büttner R, Frenzel LP, Kashkar H, and Reinhardt HC
- Subjects
- Animals, B-Lymphocytes pathology, Cell Transformation, Neoplastic genetics, Cell Transformation, Neoplastic pathology, Humans, Lymphoma, Large B-Cell, Diffuse genetics, Lymphoma, Large B-Cell, Diffuse pathology, Mice, Mice, Transgenic, Myeloid Differentiation Factor 88 genetics, Neoplasms, Experimental genetics, Neoplasms, Experimental pathology, Proto-Oncogene Proteins c-bcl-2 biosynthesis, Proto-Oncogene Proteins c-bcl-2 genetics, B-Lymphocytes metabolism, Cell Transformation, Neoplastic metabolism, Lymphoma, Large B-Cell, Diffuse metabolism, Mutation, Missense, Myeloid Differentiation Factor 88 biosynthesis, Neoplasms, Experimental metabolism
- Abstract
The adaptor protein MYD88 is critical for relaying activation of Toll-like receptor signaling to NF-κB activation. MYD88 mutations, particularly the p.L265P mutation, have been described in numerous distinct B-cell malignancies, including diffuse large B-cell lymphoma (DLBCL). Twenty-nine percent of activated B-cell-type DLBCL (ABC-DLBCL), which is characterized by constitutive activation of the NF-κB pathway, carry the p.L265P mutation. In addition, ABC-DLBCL frequently displays focal copy number gains affecting BCL2 Here, we generated a novel mouse model in which Cre-mediated recombination, specifically in B cells, leads to the conditional expression of Myd88(p.L252P) (the orthologous position of the human MYD88(p.L265P) mutation) from the endogenous locus. These mice develop a lymphoproliferative disease and occasional transformation into clonal lymphomas. The clonal disease displays the morphologic and immunophenotypical characteristics of ABC-DLBCL. Lymphomagenesis can be accelerated by crossing in a further novel allele, which mediates conditional overexpression of BCL2 Cross-validation experiments in human DLBCL samples revealed that both MYD88 and CD79B mutations are substantially enriched in ABC-DLBCL compared with germinal center B-cell DLBCL. Furthermore, analyses of human DLBCL genome sequencing data confirmed that BCL2 amplifications frequently co-occurred with MYD88 mutations, further validating our approach. Finally, in silico experiments revealed that MYD88-mutant ABC-DLBCL cells in particular display an actionable addiction to BCL2. Altogether, we generated a novel autochthonous mouse model of ABC-DLBCL that could be used as a preclinical platform for the development and validation of novel therapeutic approaches for the treatment of ABC-DLBCL.
- Published
- 2016
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