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
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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“Additionally, RhoH was also found to promote ZAP−70-induced BCR signalling, which has been implicated in CLL [33,68,69,70].”
From The Role of RhoH in TCR Signalling and Its Involvement in Diseases (2021) · cites this paper as [70]
Citations
Cites
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COSMIC: the Catalogue Of Somatic Mutations In Cancer
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Notch signalling: a simple pathway becomes complex
Bray, S. J. (2006) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2009 · Cited by 2,620
Stephens, L., Anderson, K. E., Stokoe, D., Erdjument‐Bromage, H., Painter, G. F., Holmes, A. B., Gaffney, P. R. J., Reese, C. B., McCormick, F. P., Tempst, P., et al. (1998) · Science · doi:10.1126/science.279.5351.710 · Cited by 1,061
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Mutational loss of PTEN induces resistance to NOTCH1 inhibition in T-cell leukemia
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Notch signaling controls multiple steps of pancreatic differentiation
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Role that phosphorylation of GSK3 plays in insulin and Wnt signalling defined by knockin analysis
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Glutathione primes t cell metabolism for inflammation
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Cited by
The Role of RhoH in TCR Signalling and Its Involvement in Diseases
Ahmad Mokhtar, A. M., Hashim, I. F., Mohd Zaini Makhtar, M., Salikin, N. H., & Amin-Nordin, S. (2021) · Cells · doi:10.3390/cells10040950 · Cited by 25
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
- Cited by
- 87
- References
- 58
- Language
- en
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- CoChat. (2026). Citation check: Active Akt signaling triggers CLL toward Richter transformation via overactivation of Notch1. https://app.cochat.ai/papers/10.1182/blood.2020005734
- The paper
- 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., . . . Wunderlich, F. T. (2021). Active Akt signaling triggers CLL toward Richter transformation via overactivation of Notch1. Blood. https://doi.org/10.1182/blood.2020005734
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Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
Semantic Scholar’s data is described in: Kinney, R., et al. (2023). The Semantic Scholar Open Data Platform. arXiv:2301.10140.
