Grey, William;
Rio-Machin, Ana;
Casado, Pedro;
Grönroos, Eva;
Ali, Sara;
Miettinen, Juho J;
Bewicke-Copley, Findlay;
... Bonnet, Dominique; + view all
(2022)
CKS1 inhibition depletes leukemic stem cells and protects healthy hematopoietic stem cells in acute myeloid leukemia.
Science Translational Medicine
, 14
(650)
, Article eabn3248. 10.1126/scitranslmed.abn3248.
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Abstract
Acute myeloid leukemia (AML) is an aggressive hematological disorder comprising a hierarchy of quiescent leukemic stem cells (LSCs) and proliferating blasts with limited self-renewal ability. AML has a dismal prognosis, with extremely low 2-year survival rates in the poorest cytogenetic risk patients, primarily due to the failure of intensive chemotherapy protocols to deplete LSCs and toxicity of therapy toward healthy hematopoietic cells. We studied the role of cyclin-dependent kinase regulatory subunit 1 (CKS1)-dependent protein degradation in primary human AML and healthy hematopoiesis xenograft models in vivo. Using a small-molecule inhibitor (CKS1i), we demonstrate a dual role for CKS1-dependent protein degradation in reducing patient-derived AML blasts in vivo and, importantly, depleting LSCs, whereas inhibition of CKS1 has the opposite effect on normal hematopoiesis, protecting normal hematopoietic stem cells from chemotherapeutic toxicity. Proteomic analysis of responses to CKS1i in our patient-derived xenograft mouse model demonstrate that inhibition of CKS1 in AML leads to hyperactivation of RAC1 and accumulation of lethal reactive oxygen species, whereas healthy hematopoietic cells enter quiescence in response to CKS1i, protecting hematopoietic stem cells. Together, these findings demonstrate that CKS1-dependent proteostasis is a key vulnerability in malignant stem cell biology.
| Type: | Article |
|---|---|
| Title: | CKS1 inhibition depletes leukemic stem cells and protects healthy hematopoietic stem cells in acute myeloid leukemia |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1126/scitranslmed.abn3248 |
| Publisher version: | https://doi.org/10.1126/scitranslmed.abn3248 |
| Language: | English |
| Additional information: | This version is the author accepted manuscript. For information on re-use, please refer to the publisher's terms and conditions. // This works was supported partly by Cancer Research UK (FC001115 to D.B.), the U.K. Medical Research Council (FC001115 to D.B.), the Wellcome Trust (FC001115 to D.B.), a CRUK program grant (C15966/A24375 to J.F. and D.B.), and Leukemia UK (2021/JGF/002 to W.G.). For the purpose of Open Access, the authors have applied a CC BY public copyright license to any author-accepted manuscript version arising from this submission. |
| Keywords: | Animals, CDC2-CDC28 Kinases, Hematopoiesis, Hematopoietic Stem Cells, Humans, Leukemia, Myeloid, Acute, Mice, Neoplastic Stem Cells, Proteomics |
| UCL classification: | UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Oncology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10151766 |
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