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Cited by 87

The DOI matches its Crossref record; 58 of the 58 references it cites were found in a registry or an index.

Active Akt signaling triggers CLL toward Richter transformation via overactivation of Notch1

Kohlhaas, Vivien, Blakemore, Stuart James, Al-Maarri, Mona, Nickel, Nadine, Pal, Martin, Roth, Andreas, Hövelmeyer, Nadine, Schäfer, Stephan C., Knittel, Gero, Lohneis, Philipp, Nikolic, Milos, Wiederstein, Janica L., Franitza, Marek, Georgomonolis, Theodoros, Reinart, Nina, Herling, Marco, Herling, Carmen, Hartmann, Elena M., Rosenwald, Andreas, Klapper, Wolfram, Büttner, Reinhard, Moia, Riccardo, Rossi, Davide, Boldorini, Renzo, Gaidano, Gianluca, Frenzel, Lukas P., Reinhardt, Hans Christian, Brüning, Jens C., Hallek, Michael, Krüger, Marcus, Peifer, Martin, Pallasch, Christian P., Wunderlich, F. Thomas·2021·Blood
DOI 10.1182/blood.2020005734
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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.

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Crossref · 10.1182/blood.2020005734

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Metadata

Authors
Kohlhaas, V., Blakemore, S. J., Al-Maarri, M., Nickel, N., Pal, M., Roth, A., Hövelmeyer, N., Schäfer, S. C., Knittel, G., Lohneis, P., Nikolic, M., Wiederstein, J. L., Franitza, M., Georgomonolis, T., Reinart, N., Herling, M., Herling, C., Hartmann, E. M., Rosenwald, A., Klapper, W., Büttner, R., Moia, R., Rossi, D., Boldorini, R., Gaidano, G., Frenzel, L. P., Reinhardt, H. C., Brüning, J. C., Hallek, M., Krüger, M., Peifer, M., Pallasch, C. P., & Wunderlich, F. T.
Affiliations
  • Max Planck Institute for Metabolism Research, Cologne, Germany;
  • Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Cologne, Germany;
  • Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg, University Mainz, Mainz, Germany;
  • Institute of Pathology,
  • Center for Molecular Medicine Cologne (CMMC), Cologne, Germany;
  • Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany;
  • Institute of Pathology, University of Würzburg, and Comprehensive Cancer Center Mainfranken, Würzburg, Germany;
  • Department of Pathology, University Hospital of Schleswig-Holstein, Kiel, Germany;
  • Division of Pathology, Department of Health Science, University of Piemonte Orientale (UPO), Novara, Italy;
  • Division of Hematology, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland;
  • Università del Piemonte Orientale, Department of Translational Medicine, Novara, Italy; and
ORCID
Venue
Blood
Publisher
American Society of Hematology
Published
2021-02-04
Volume
137
Issue
5
Pages
646-660
ISSN
  • 0006-4971
  • 1528-0020
DOI
10.1182/blood.2020005734
Cited by
87
References
58
Language
en

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