CKS1 inhibition depletes leukemic stem cells and protects healthy hematopoietic stem cells in acute myeloid leukemia

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http://hdl.handle.net/10138/346375

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Grey , W , Rio-Machin , A , Casado , P , Gronroos , E , Ali , S , Miettinen , J J , Bewicke-Copley , F , Parsons , A , Heckman , C A , Swanton , C , Cutillas , P R , Gribben , J , Fitzgibbon , J & Bonnet , D 2022 , ' CKS1 inhibition depletes leukemic stem cells and protects healthy hematopoietic stem cells in acute myeloid leukemia ' , Science translational medicine , vol. 14 , no. 650 , 3248 . https://doi.org/10.1126/scitranslmed.abn3248

Title: CKS1 inhibition depletes leukemic stem cells and protects healthy hematopoietic stem cells in acute myeloid leukemia
Author: Grey, William; Rio-Machin, Ana; Casado, Pedro; Gronroos, Eva; Ali, Sara; Miettinen, Juho J.; Bewicke-Copley, Findlay; Parsons, Alun; Heckman, Caroline A.; Swanton, Charles; Cutillas, Pedro R.; Gribben, John; Fitzgibbon, Jude; Bonnet, Dominique
Contributor organization: University of Helsinki
Institute for Molecular Medicine Finland
Doctoral Programme Brain & Mind
Doctoral Programme in Integrative Life Science
Doctoral Programme in Drug Research
Doctoral Programme in Biomedicine
Research Programs Unit
Date: 2022-06-22
Language: eng
Number of pages: 14
Belongs to series: Science translational medicine
ISSN: 1946-6234
DOI: https://doi.org/10.1126/scitranslmed.abn3248
URI: http://hdl.handle.net/10138/346375
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 hyper-activation 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.
Subject: SMALL-MOLECULE INHIBITORS
INTENSIVE CHEMOTHERAPY
SELF-RENEWAL
AML CELLS
OVEREXPRESSION
EXPRESSION
CANCER
PEVONEDISTAT
AZACITIDINE
VENETOCLAX
1182 Biochemistry, cell and molecular biology
Peer reviewed: Yes
Usage restriction: openAccess
Self-archived version: acceptedVersion


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