Role of Cks1 for l-dependent and -indepentend cell cycle regulation, survival and quiescence in normal and leukemic hematopoiesis
Final Report Abstract
We identified Cks1 as an essential regulator of HSC fate operating upstream of the CKI p27, p21 and p57, and the Rb family member p130. Cks1 loss prominently affects the most immature CD150+ LSK HSC compartment by inhibiting exit from quiescence and cell cycling, and protects more mature HPC from apoptosis. Our analyses revealed that p27 is an essential downstream target of the SCFSkp2-Cks1 complex in the regulation of early hematopoiesis. Most likely all SCFSkp2/Cks1 CKI targets and p130 are involved in the HSC/HPC control. Only genetic in vivo studies involving composite gene kockout mice would allow deciphering this complex network. In CML, Cks1 is overexpressed. Cks1 is a mediator of Bcr-Ablinduced clonogenic activity, where Bcr-Abl expression also involves high Myc levels. Therefore Cks1 is proposed to be a central intermediate for normal and oncogene-induced hematopoietic cell cycle regulation. Cks1 thus represents a therapeutic target in various hematologic malignancies.
Publications
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(2014) Disruption of the PRKCD-FBXO25-HAX-1 axis attenuates the apoptotic response and drives lymphomagenesis, Nature medicine 20, 1401-1409
Baumann, U., Fernandez-Saiz, V., Rudelius, M., Lemeer, S., Rad, R., Knorn, A. M., Slawska, J., Engel, K., Jeremias, I., Li, Z., Tomiatti, V., Illert, A. L., Targosz, B. S., Braun, M., Perner, S., Leitges, M., Klapper, W., Dreyling, M., Miething, C., Lenz, G., Rosenwald, A., Peschel, C., Keller, U., Kuster, B., and Bassermann, F.
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(2014) Mycinduced SUMOylation is a therapeutic vulnerability for B-cell lymphoma, Blood 124, 2081-2090
Hoellein, A., Fallahi, M., Schoeffmann, S., Steidle, S., Schaub, F. X., Rudelius, M., Laitinen, I., Nilsson, L., Goga, A., Peschel, C., Nilsson, J. A., Cleveland, J. L., and Keller, U.
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(2015) Cks1 is a critical regulator of hematopoietic stem cell quiescence and cycling, operating upstream of Cdk inhibitors, Oncogene 34, 4347-4357
Tomiatti, V., Istvanffy, R., Pietschmann, E., Kratzat, S., Hoellein, A., Quintanilla-Fend, L., von Bubnoff, N., Peschel, C., Oostendorp, R. A., and Keller, U.
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(2015) Disclosing the CXCR4 Expression in Lymphoproliferative Diseases by Targeted Molecular Imaging, Theranostics 5, 618-630
Wester, H. J., Keller, U., Schottelius, M., Beer, A., Philipp-Abbrederis, K., Hoffmann, F., Simecek, J., Gerngross, C., Lassmann, M., Herrmann, K., Pellegata, N., Rudelius, M., Kessler, H., and Schwaiger, M.
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(2015) In vivo hematopoietic Myc activation directs a transcriptional signature in endothelial cells within the bone marrow microenvironment, Oncotarget 6, 21827-39
Franke, K., Vilne, B., Da Costa, O., Rudelius, M., Peschel, C., Oostendorp, R. A., and Keller, U.
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(2015) In vivo molecular imaging of chemokine receptor CXCR4 expression in patients with advanced multiple myeloma, EMBO molecular medicine 7, 477-487
Philipp-Abbrederis, K., Herrmann, K., Knop, S., Schottelius, M., Eiber, M., Luckerath, K., Pietschmann, E., Habringer, S., Gerngross, C., Franke, K., Rudelius, M., Schirbel, A., Lapa, C., Schwamborn, K., Steidle, S., Hartmann, E., Rosenwald, A., Kropf, S., Beer, A. J., Peschel, C., Einsele, H., Buck, A. K., Schwaiger, M., Gotze, K., Wester, H. J., and Keller, U.
