Complementary approaches define the metabolic features that accompany Richter syndrome transformation
Richter syndrome (RS) is the transformation of chronic lymphocytic leukemia (CLL) into a high-grade lymphoma with previously unknown metabolic features. Transcriptomic data from primary CLL and RS samples, as well as RS-patient-derived xenografts, highlighted cellular metabolism as one of the most significant differentially expressed processes. Activity assays of key enzymes confirmed the intense metabolic rewiring of RS cells, which is characterized by an elevated rate of Krebs cycle, oxidative phosphorylation, and glutamine metabolism. These pathways were sustained by increased uptake of glucose and glutamine, two critical substrates for these cells. Moreover, RS cells showed activation of anabolic processes that resulted in the synthesis of nucleotides and lipids necessary to support their high proliferation. Exposure to drugs targeting PI3K and NF-kB, two master regulators of cellular metabolism, resulted in the shutdown of ATP production and glycolysis. Overall, these data suggest that metabolic rewiring characterizes the transformation of CLL into RS, presenting new translational opportunities.
Authors
- Andrea Iannello (ORCID: https://orcid.org/0000-0001-8940-1406)
- Richard R. Furman (ORCID: https://orcid.org/0000-0003-1677-7626)
- Matilde Micillo
- Tiziana Vaisitti (ORCID: https://orcid.org/0000-0002-3375-6985)
- Peter Möller (ORCID: https://orcid.org/0000-0002-2021-1249)
- Nadia Bertola (ORCID: https://orcid.org/0000-0003-4591-3260)
- John Nathan Allan (ORCID: https://orcid.org/0000-0002-2088-0899)
- Lorenzo Brandimarte (ORCID: https://orcid.org/0000-0001-9015-8407)
- Silvia Bruno (ORCID: https://orcid.org/0000-0001-8799-8325)
- Silvia Deaglio (ORCID: https://orcid.org/0000-0003-0632-5036)
- Silvia Ravera (ORCID: https://orcid.org/0000-0002-0803-1042)
- Chiara Lavarello (ORCID: https://orcid.org/0000-0002-5543-5285)
- Kevin Mellert (ORCID: https://orcid.org/0000-0001-6338-1857)
- Andrea Petretto (ORCID: https://orcid.org/0000-0001-7811-8517)
- Giulio Ferrero (ORCID: https://orcid.org/0000-0002-4580-0680)
- Giulia Omezzolli
- Francesco Edoardo Vallone (ORCID: https://orcid.org/0009-0006-0824-1038)
- Nicole Grinovero
Institutions
- Cornell University (US)
- Istituto Giannina Gaslini (IT)
- Presbyterian Hospital (US)
- Department of Medical Sciences (BY)
- Ospedale Policlinico San Martino (IT)
- University Hospital Ulm (DE)
- University of Turin (IT)
- University of Genoa (IT)
Publication Details
- Journal
- Cellular and Molecular Life Sciences
- Published
- 2025-04-09
- DOI
- https://doi.org/10.1007/s00018-025-05670-4
- Citations
- 2
- Primary Topic
- Metabolism, Diabetes, and Cancer
- Type
- article
- Field-Weighted Citation Impact
- 1.61
Funders
- Università degli Studi di Torino