Function of tyrosine kinases Lyn and Btk in high-risk CLL
Final Report Abstract
Tremendous advances regarding the therapy of CLL have been made with the development of small molecule kinase inhibitors targeting the B cell receptor (BCR)-associated kinases. Prominent examples for this class of agents are the successful treatment of CLL with the BTK inhibitor ibrutinib or the PI3Kδ inhibitor idelalisib. More recently, accumulating evidence has been created that essential effects of these inhibitors are not mediated by targeting the malignant B cell population directly but rather by shaping the dialogue of tumor cells with the microenvironment, the efficacy of BCR-associated kinase inhibition depends not only on the inhibition of B cell-autonomous functions but also by affecting several cell types within the lymphoid tumor microenvironment. Importantly, clinical observations are strongly supporting this evidence, because CLL patients treated with these kinase inhibitors showed a longlasting lymphocytosis following the rapid decrease of lymphadenopathy, indicating that leukemic cells lose their contact to the tumor microenvironment and undergo a relocation from lymphoid homing organs to the periphery. Given the broad expression of BCR-associated kinases such as Lyn and Btk in all tissues, their molecular functions, and particularly the effects of their inhibition in CLL should inevitably be studied beyond B cell biology. During the KFO funding periods, we created a new perspective on the role of these kinases by the use of mouse models, where the established CLL model, the Eµ-TCL1 transgenic mice were intercrossed with Lyn or Btk knockout mice. Our experiments surprisingly revealed that these kinases are crucial for the formation of a leukemic niche that fosters CLL development. In experiments where we transplanted leukemic cells into wild type versus Lyn- or Btk-deficient mice, the absence of Lyn or Btk in recipient mice significantly delayed leukemic progression, eventually leading to prolonged survival of the knockout recipient mice. This effect was explained at least in part by a reduced capacity of the knockout macrophages to support primary CLL cell survival. Collectively, our observations that knockout of Lyn in the TME could effectively hinder CLL development open a new avenue of research: An increased understanding of the molecular changes induced by Lyn/Btk in specific microenvironmental cell types could be used to therapeutically target its substrates and specific pathways that are essential for the expansion of CLL.
Publications
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(2015). Efficacy of phosphatidylinositol-3 kinase inhibitors with diverse isoform selectivity profiles for inhibiting the survival of chronic lymphocytic leukemia cells. Int J Cancer. Nov 1;137(9):2234-42
Göckeritz E, Kerwien S, Baumann M, Wigger M, Vondey V, Neumann L, Landwehr T, Wendtner CM, Klein C, Liu N, Hallek M, Frenzel LP, Krause G
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(2015). Mutations driving CLL and their evolution in progression and relapse. Nature Oct 22;526(7574):525-30
Landau DA, Tausch E, Taylor-Weiner AN, Stewart C, Reiter JG, Bahlo J, Kluth S, Bozic I, Lawrence M, Böttcher S, Carter SL, Cibulskis K, Mertens D, Sougnez CL, Rosenberg M, Hess JM, Edelmann J, Kless S, Kneba M, Ritgen M, Fink A, Fischer K, Gabriel S, Lander ES, Nowak MA, Döhner H, Hallek M, Neuberg D, Getz G, Stilgenbauer S, Wu CJ
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Hypoxia-induced p38 MAPK activation reduces Mcl-1 expression and facilitates sensitivity towards BH3 mimetics in chronic lymphocytic leukemia. Leukemia. 2015 Apr;29(4):981-4
Huelsemann MF, Patz M, Beckmann L, Brinkmann K, Otto T, Fandrey J, Becker HJ, Theurich S, von Bergwelt-Baildon M, Pallasch CP, Zahedi RP, Kashkar H, Reinhardt HC, Hallek M, Wendtner CM, Frenzel LP
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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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The regulatory interaction of EVI1 with the TCL1A oncogene impacts cell survival and clinical outcome in CLL. Leukemia. 2015 29(10), 2003-2014
Vasyutina, E., Boucas, J. M., Bloehdorn, J., Aszyk, C., Crispatzu, G., Stiefelhagen M, Breuer A, Mayer P, Lengerke C, Döhner H, Beutner D, Rosenwald A, Stilgenbauer S, Hallek M, Benner A, Herling M
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(2016) Cytotoxicity of the CD37 antibody BI 836826 against chronic lymphocytic leukaemia cells in combination with chemotherapeutic agents or PI3K inhibitors. Br J Haematol. Jun;173(5):791-4
Krause G, Baki I, Kerwien S, Knödgen E, Neumann L, Göckeritz E, Landwehr T, Heider KH, Hallek M
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(2016). LYN Kinase in the Tumor Microenvironment Is Essential for the Progression of Chronic Lymphocytic Leukemia. Cancer Cell, 30(4), 610-62
Nguyen PH, Fedorchenko O, Rosen N, Koch M, Barthel R, Winarski T, Florin A, Wunderlich FT, Reinart N, & Hallek M
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(2017). Establishing a chemical genetic link between Bruton tyrosine kinase activity in malignant B cells and cell functions involved in the micro-environmental dialogue. Br J Haematol, 178(6), 949-953
Gockeritz E, Vondey V, Guastafierro A, Pizevska M, Hassenruck F, Neumann L, Hallek M, & Krause G
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(2017). Two mouse models reveal an actionable PARP1 dependence in aggressive chronic lymphocytic leukemia. Nat Commun. 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 C, 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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(2020). Constitutive activation of Lyn kinase enhances BCR responsiveness, but not the development of CLL in Emicro-TCL1 mice. Blood Adv, 4(24), 6106-6116
Kohlhas V, Hallek M, & Nguyen PH
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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
