Maike Buchner - Immune Cell Signaling in Chronic Lymphocytic Leukemia
B cells are critical for adaptive immunity, but can also trigger autoimmunity or develop into malignant B cell lymphomas when signaling molecules and/or transcription factors are deregulated. The focus of my Max Eder research group is to understand how signaling perturbations in malignant and normal B cells affect their survival and/or malignant spread in order to find new treatments. A particular focus of our group is to explore whether hyperactivation of signaling pathways could represent a new therapeutic strategy in chronic lymphocytic leukemia (CLL). We have shown that acute activation of the PI3K/AKT pathway promotes cell death in transformed mature B cells, namely CLL. To exploit this therapeutically, we used inhibition of the inhibitory phosphatase SHIP1, which dramatically promotes induction of immunogenic cell death in vitro and in vivo by increasing mitochondrial metabolism and ROS formation in CLL cells (Ecker et al, 2021). Based on these findings, we are currently investigating whether transient inhibition of SHIP1 is effective in drug-resistant CLL and may increase the efficacy of immunotherapeutic approaches to overcome their current limitations in single-agent treatments for CLL. In a similar effort, we are also investigating the role of dual-specific phosphatases (DUSP proteins) that negatively regulate MAPK signaling in CLL cells. We found that the ERK1/2 phosphatase DUSP6 is highly expressed in samples from CLL patients with poor clinical prognosis, especially in CLL cases carrying MAPK-activating mutations in BRAF and KRAS, and therefore DUSP6 expression may serve as a prognostic marker for CLL. Using global phospho-proteome analysis, we found that inhibition of DUSP1/6 in CLL triggered transient ERK phosphorylation, followed by induction of the DNA damage response pathway and apoptotic cell death specifically in CLL cells. We therefore show that expression of the negative regulators DUSP1 and DUSP6 is required to balance high oncogenic MAPK signaling in CLL and prevent apoptosis. Because activation of the PI3K and MAPK signaling pathways is frequently observed during transformation of CLL cells into aggressive lymphoma, we are currently also investigating how CLL cells overcome the cell death induced by hypersignaling during the transformation process. This information could be useful in finding strategies to prevent and treat Richter's transformation, which is particularly important based on the short survival rate of Richter patients and the lack of effective and targeted treatments.
Maike Buchner received her Master in Molecular Medicine in Freiburg in 2006. She completed her PhD with honors in 2010 with the project ‚Inhibition of Microenvironmental Pathways: a Novel Therapeutic Approach in Chronic Lymphocytic Leukemia’ in the laboratory of Hendrik Veelken in Freiburg. She conducted her postdoctoral studies at the University of California, San Francisco in the laboratory if Markus Müschen. Here, she studied normal B cell development and transformation to acute lymphoblastic leukemia (ALL). She contributed to studies involving signaling thresholds in ALL and negative feedback inhibition. With these insights together with her PhD experience, her current research is focusing on negative feedback inhibition in CLL.
The focus of Maike Buchner’s research is the dissection of divergent signaling events in malignant versus normal B cells. In particular downstream of the B cell receptor and the regulation of signaling strength. Her focus is on chronic lymphocytic leukemia. Via analysis of primary patient samples and healthy donors as well as preclinical models, she investigates the impact of inhibition of negative regulators on different cell types.
- Max-Eder Fellowship, German Cancer Aid, 2nd funding period (2022)
- Max-Eder Fellowship, German Cancer Aid (2016)
- Abstract Achievement Award, American Society of Hematology (2015)
- Travel grant for job interviews (Rückkehrer Stipendium DAAD) (2014)
- Abstract Achievement Award, American Society of Hematology (2013)
- Abstract Achievement Award, American Society of Hematology (2012)
- Award for outstanding achievements during Graduation in Molecular Medcine, University Medical School Freiburg (2010)
- PhD Scholarship, University Medical School Freiburg (2006)
Ecker, V.*, Stumpf, M.*, Brandmeier, L., Neumayer, T., Pfeuffer, L., Engleitner, T., Ringshausen, I., Nelson, N., Jucker, M., Wanninger, S., Zenz, T., Wendtner, C., Manske, K., Steiger, K., Rad, R., Muschen, M., Ruland, J., Buchner, M. (2021). Targeted PI3K/AKT-hyperactivation induces cell death in chronic lymphocytic leukemia. Nat Commun 12, 3526.
Alankus, B.*, Ecker, V.*, Vahl, N., Braun, M., Weichert, W., Macher-Goppinger, S., Gehring, T., Neumayer, T., Zenz, T., Buchner, M.#, Ruland, J.# (2021). Pathological RANK signaling in B cells drives autoimmunity and chronic lymphocytic leukemia. J Exp Med 218.
Patzelt, T., Keppler, S.J., Gorka, O., Thoene, S., Wartewig, T., Reth, M., Forster, I., Lang, R., Buchner, M.§, Ruland, J.§ (2018). Foxp1 controls mature B cell survival and the development of follicular and B-1 B cells. Proc Natl Acad Sci U S A 115, 3120-3125.
Shojaee, S., Chan, L.N., Buchner, M., Cazzaniga, V., Cosgun, K.N., Geng, H., Qiu, Y.H., von Minden, M.D., Ernst, T., Hochhaus, A., Cazzaniga, G., Melnick, A., Kornblau, S.M., Graeber, T.G., Wu, H., Jumaa, H., Muschen, M. (2016). PTEN opposes negative selection and enables oncogenic transformation of pre-B cells. Nat Med 22, 379-87.
Buchner, M.§, Park, E., Geng, H., Klemm, L., Flach, J., Passegue, E., Schjerven, H., Melnick, A., Paietta, E., Kopanja, D., Raychaudhuri, P., Muschen, M. (2015). Identification of FOXM1 as a therapeutic target in B-cell lineage acute lymphoblastic leukaemia. Nat Commun 6, 6471. §Corresponding author
Chen, Z.*, Shojaee, S.*, Buchner, M., Geng, H., Lee, J.W., Klemm, L., Titz, B., Graeber, T.G., Park, E., Tan, Y.X., Satterthwaite, A., Paietta, E., Hunger, S.P., Willman, C.L., Melnick, A., Loh, M.L., Jung, J.U., Coligan, J.E., Bolland, S., Mak, T.W., Limnander, A., Jumaa, H., Reth, M., Weiss, A., Lowell, C.A., Muschen, M. (2015). Signalling thresholds and negative B-cell selection in acute lymphoblastic leukaemia. Nature 521, 357-61.
Duhren-von Minden, M., Ubelhart, R., Schneider, D., Wossning, T., Bach, M.P., Buchner, M., Hofmann, D., Surova, E., Follo, M., Kohler, F., Wardemann, H., Zirlik, K., Veelken, H., Jumaa, H. (2012). Chronic lymphocytic leukaemia is driven by antigen-independent cell-autonomous signalling. Nature 489, 309-12.
Buchner, M., Baer, C., Prinz, G., Dierks, C., Burger, M., Zenz, T., Stilgenbauer, S., Jumaa, H., Veelken, H., Zirlik, K. (2010). Spleen tyrosine kinase inhibition prevents chemokine- and integrin-mediated stromal protective effects in chronic lymphocytic leukemia. Blood 115, 4497-506.
Buchner, M., Brantner, P., Stickel, N., Prinz, G., Burger, M., Bar, C., Dierks, C., Pfeifer, D., Ott, A., Mertelsmann, R., Gribben, J.G., Veelken, H., Zirlik, K. (2010). The microenvironment differentially impairs passive and active immunotherapy in chronic lymphocytic leukaemia - CXCR4 antagonists as potential adjuvants for monoclonal antibodies. Br J Haematol 151, 167-78.
Buchner, M., Fuchs, S., Prinz, G., Pfeifer, D., Bartholome, K., Burger, M., Chevalier, N., Vallat, L., Timmer, J., Gribben, J.G., Jumaa, H., Veelken, H., Dierks, C., Zirlik, K. (2009). Spleen tyrosine kinase is overexpressed and represents a potential therapeutic target in chronic lymphocytic leukemia. Cancer Res 69, 5424-
Dr. Maike Buchner
Technical University of Munich
School of Medicine
Institute for Clinical Chemistry and Pathobiochemistry
Phone: +49 89 4140 9255