Elucidation of the PI3K/AKT pathway in the transformation and progression of CLL
Final Report Abstract
Richter’s transformation (RT) is an aggressive lymphoma which 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 occurs both in high-risk CLL patients harboring TP53 and NOTCH1 mutations as well as in RT patients. Genetic over-activation of Akt in the murine Eµ-TCL1 CLL mouse model resulted in CLL 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 DLBCL. Multi-omics assessment by phosphoproteomic/proteomic and single-cell transcriptomic profiles of this Akt-induced murine RT revealed a S100-protein-defined subcluster of highly aggressive lymphoma cells, which 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 towards aggressive lymphoma by inducing Notch signaling between RT cells and microenvironmental T cells.
Publications
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miRs-138 and -424 control palmitoylationdependent CD95-mediated cell death by targeting acyl protein thioesterases 1 and 2 in CLL. Blood. 2015 May 7;125(19):2948-57
Berg V, Rusch M, Vartak N, Jüngst C, Schauss A, Waldmann H, Hedberg C, Pallasch CP, Bastiaens PI, Hallek M, Wendtner CM, Frenzel LP
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B-cell-specific conditional expression of Myd88p.L252P leads to the development of diffuse large B-cell lymphoma in mice. Blood. 2016 Jun 2;127(22):2732-41
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; German International Cancer Genome Consortium Molecular Mechanisms in Malignant Lymphoma by Sequencing Project Consortium, 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, Reinhardt HC
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Concepts of Chronic Lymphocytic Leukemia Pathogenesis: DNA Damage Response and Tumor Microenvironment. Oncol Res Treat. 2016;39(1-2):9-16
Frenzel LP, Reinhardt HC, Pallasch CP
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LYN Kinase in the Tumor Microenvironment Is Essential for the Progression of Chronic Lymphocytic Leukemia. Cancer Cell. 2016 Oct 10;30(4):610-622
Nguyen PH, Fedorchenko O, Rosen N, Koch M, Barthel R, Winarski T, Florin A, Wunderlich FT, Reinart N, Hallek M
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Rewired NFκB signaling as a potentially actionable feature of activated B-cell-like diffuse large B-cell lymphoma. Eur J Haematol. 2016 Dec;97(6):499-510
Knittel G, Liedgens P, Korovkina D, Pallasch CP, Reinhardt HC
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Two mouse models reveal an actionable PARP1 dependence in aggressive chronic lymphocytic leukemia. Nat Commun. 2017 Jul 28;8(1):153
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, Reinhardt HC
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Clonal dynamics towards the development of venetoclax resistance in chronic lymphocytic leukemia. Nat Commun. 2018 Feb 20;9(1):727
Herling CD, Abedpour N, Weiss J, Schmitt A, Jachimowicz RD, Merkel O, Cartolano M, Oberbeck S, Mayer P, Berg V, Thomalla D, Kutsch N, Stiefelhagen M, Cramer P, Wendtner CM, Persigehl T, Saleh A, Altmüller J, Nürnberg P, Pallasch CP, Achter V, Lang U, Eichhorst B, Castiglione R, Schäfer SC, Büttner R, Kreuzer KA, Reinhardt HC, Hallek M, Frenzel LP, Peifer M
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Tumor Metabolism as a Regulator of Tumor-Host Interactions in the B-Cell Lymphoma Microenvironment-Fueling Progression and Novel Brakes for Therapy. Int J Mol Sci. 2019 Aug 26;20(17):4158
Beielstein AC, Pallasch CP
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Macrophage-Mediated Antibody Dependent Effector Function in Aggressive B-Cell Lymphoma Treatment is Enhanced by Ibrutinib via Inhibition of JAK2. Cancers (Basel). 2020 Aug 15;12(8):2303
Barbarino V, Henschke S, Blakemore SJ, Izquierdo E, Michalik M, Nickel N, Möllenkotte I, Vorholt D, Müller L, Brinker R, Fedorchenko O, Mikhael N, Seeger-Nukpezah T, Hallek M, Pallasch CP
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Active Akt signaling triggers CLL toward Richter transformation via overactivation of Notch1. Blood. 2021 Feb 4;137(5):646-660
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, Wunderlich FT
