Ribosomal protein control of hematopoietic stem cell transformation through regulation of metabolism
We report here that expression of the ribosomal protein RPL22 is frequently reduced in human myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML), and reduced RPL22 expression is associated with worse outcomes. Mice null for Rpl22 display characteristics of an MDS-like syndrome and develop leukemia at an accelerated rate. Rpl22-deficient mice also display enhanced hematopoietic stem cell (HSC) self-renewal and obstructed differentiation potential, which arises not from reduced protein synthesis but from altered metabolism, including increased fatty acid oxidation (FAO) and a striking induction of the stemness factor Lin28b in the resulting leukemia. Lin28b promotes a substantial increase in lipid content, upon which the survival of Rpl22-deficient leukemias depends. Altogether, these findings reveal that Rpl22 insufficiency enhances the leukemia potential of HSCs through regulation of FAO and promotes leukemogenesis through Lin28b promotion of lipid synthesis.
Authors
- Dinesh Kumar Singh (ORCID: https://orcid.org/0000-0002-3594-2431)
- David L. Wiest (ORCID: https://orcid.org/0000-0002-0792-3188)
- Andrea Pellagatti (ORCID: https://orcid.org/0000-0002-6122-0221)
- Kith Pradhan (ORCID: https://orcid.org/0000-0001-7089-1652)
- Orsi Giricz (ORCID: https://orcid.org/0000-0002-1328-3682)
- Brian Keith Kennedy (ORCID: https://orcid.org/0000-0002-5754-1874)
- Michele Rhodes
- Shanna R. Sprinkle (ORCID: https://orcid.org/0000-0002-3595-8660)
- Minshi Wang (ORCID: https://orcid.org/0000-0002-0225-0586)
- Susan A. Shinton (ORCID: https://orcid.org/0000-0003-2649-1904)
- Bridget Aylward (ORCID: https://orcid.org/0000-0002-0377-2028)
- Monika Verma (ORCID: https://orcid.org/0000-0002-1873-1851)
- Amit Verma (ORCID: https://orcid.org/0000-0002-5408-1673)
- Jacqueline Boultwood (ORCID: https://orcid.org/0000-0002-4330-2928)
- Sarah Aminov
- Joshua L. West (ORCID: https://orcid.org/0000-0003-1670-8196)
- Stephen Matthew Sykes (ORCID: https://orcid.org/0000-0002-7330-0106)
- Jeffrey Tyner (ORCID: https://orcid.org/0000-0002-2133-0960)
- Cristina Montagna (ORCID: https://orcid.org/0000-0003-2343-5851)
- Ulrich G. Steidl (ORCID: https://orcid.org/0000-0002-9458-1795)
- Billy Truong (ORCID: https://orcid.org/0000-0002-5204-2355)
- Shawn P. Fahl (ORCID: https://orcid.org/0000-0002-0489-2048)
- K.H. Ramesh (ORCID: https://orcid.org/0009-0007-1081-2642)
- Bryan Harris (ORCID: https://orcid.org/0000-0001-5186-4851)
- Rachael Price
- Michael A. Holinstat (ORCID: https://orcid.org/0000-0001-5100-1933)
- Suraj Peri (ORCID: https://orcid.org/0000-0002-1909-8218)
- Jaqueline Perrigoue
- Yong Zhang (ORCID: https://orcid.org/0000-0002-2692-5437)
- Rachel Kessel
Institutions
- University of North Carolina at Chapel Hill (US)
- Fox Chase Cancer Center (US)
- Albert Einstein College of Medicine (US)
- Montefiore Medical Center (US)
- Oregon Health & Science University (US)
- National University of Singapore (SG)
- Duke University (US)
- Washington University in St. Louis (US)
- University of Michigan (US)
- John Radcliffe Hospital (GB)
- Michigan Medicine (US)
Publication Details
- Journal
- Cell Reports
- Published
- 2025-12-01
- DOI
- https://doi.org/10.1016/j.celrep.2025.116688
- Primary Topic
- Acute Myeloid Leukemia Research
- Type
- article
- Field-Weighted Citation Impact
- 0.00