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

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.

• Authors: Vivien Kohlhaas, Stuart James Blakemore, Mona Al-Maarri, Nadine Nickel, Martin Pal, Andreas Roth, Nadine Hövelmeyer, Stephan C Schäfer, Gero Knittel, Philipp Lohneis, Milos Nikolic, Janica L Wiederstein, Marek Franitza, Theodoros Georgomonolis, Nina Reinart, Marco Herling, Carmen Herling, Elena M Hartmann, Andreas Rosenwald, Wolfram Klapper, Reinhard Büttner, Riccardo Moia, Davide Rossi, Renzo Boldorini, Gianluca Gaidano, Lukas P Frenzel, Hans Christian Reinhardt, Jens C Brüning, Michael Hallek, Marcus Krüger, Martin Peifer, Christian P Pallasch, F Thomas Wunderlich
• Journal: Blood (Blood) Vol. 137 Issue 5 Pg. 646-660 (02 04 2021) ISSN: 1528-0020 [Electronic] United States
• PMID: 33538798 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021 by The American Society of Hematology.

Chemical References

• NOTCH1 protein, human
• Neoplasm Proteins
• Phosphoproteins
• Receptor, Notch1
• Receptors, Antigen, B-Cell
• TP53 protein, human
• Tumor Suppressor Protein p53
• AKT1 protein, human
• Akt1 protein, mouse
• Proto-Oncogene Proteins c-akt

Topics

• Animals
• Clonal Evolution
• Disease Progression
• Enzyme Activation
• Gene Expression Regulation, Neoplastic
• Genes, p53
• Leukemia, Lymphocytic, Chronic, B-Cell (genetics, pathology, physiopathology)
• Lymphocytes, Tumor-Infiltrating (immunology)
• Lymphoma, Large B-Cell, Diffuse (genetics, pathology, physiopathology)
• Mice
• Mice, Inbred C57BL
• Neoplasm Proteins (physiology)
• Phenotype
• Phosphoproteins (physiology)
• Proto-Oncogene Proteins c-akt (genetics, physiology)
• Receptor, Notch1 (physiology)
• Receptors, Antigen, B-Cell (immunology)
• Signal Transduction (physiology)
• Transcriptome
• Tumor Microenvironment
• Tumor Suppressor Protein p53 (physiology)
• Up-Regulation