Ex vivo modelling reveals low levels of CKS1 inhibition boost haematopoiesis via AKT/Foxo1 signalling

TY - JOUR

T1 - Ex vivo modelling reveals low levels of CKS1 inhibition boost haematopoiesis via AKT/Foxo1 signalling

AU - Miranda, Juliana Fabiani

AU - Rogerson, Adam

AU - Guthrie, Megan

AU - Kaur, Kimrun

AU - Apperley, Emma

AU - Dunne, Mary Catherine

AU - Shridokar, Navin

AU - Khan, Anjum

AU - Grey, William

N1 - © 2025 Published by Elsevier Inc. on behalf of International Society for Experimental Hematology. This is an author-produced version of the published paper. Uploaded in accordance with the University’s Research Publications and Open Access policy.

PY - 2025/6/11

Y1 - 2025/6/11

N2 - Hematopoietic stem cells (HSCs) are rare cells residing at the top of the haematopoietic hierarchy capable of reconstituting all blood cell populations through their ability of self-renewal and differentiation. Their ability to maintain haematopoiesis can be majorly depleted by chemotherapeutic agents, leading to a long-term bone marrow injury. However, pre-clinical studies have focused on the acute effects of chemotherapy, leaving the lasting impact on healthy cells poorly understood. To study this, we combined rapid ex vivo models to study the long-term/late-stage effects of a cyclin-dependent kinase subunit 1 (CKS1) inhibitor. Inhibition of CKS1 has been shown to protect healthy HSCs from chemotherapy during acute myeloid leukaemia, and here we show a dose-dependent role of CKS1 inhibition on haematopoiesis, either boosting B lymphopoiesis or ablating HSC proliferation capacity, dependent on the context. Mechanistically, low doses of the CKS1 inhibitor (CKS1i) activates Foxo1 signalling potentiating B-cell differentiation, but impairing HSC proliferation. These results reveal a novel role for the SCF-CKS1 complex in boosting haematopoiesis and propose the use of rapid ex vivo models to investigate the long-term effects of chemotherapeutic treatments targeting HSCs with the potential of reducing late adverse effects.

AB - Hematopoietic stem cells (HSCs) are rare cells residing at the top of the haematopoietic hierarchy capable of reconstituting all blood cell populations through their ability of self-renewal and differentiation. Their ability to maintain haematopoiesis can be majorly depleted by chemotherapeutic agents, leading to a long-term bone marrow injury. However, pre-clinical studies have focused on the acute effects of chemotherapy, leaving the lasting impact on healthy cells poorly understood. To study this, we combined rapid ex vivo models to study the long-term/late-stage effects of a cyclin-dependent kinase subunit 1 (CKS1) inhibitor. Inhibition of CKS1 has been shown to protect healthy HSCs from chemotherapy during acute myeloid leukaemia, and here we show a dose-dependent role of CKS1 inhibition on haematopoiesis, either boosting B lymphopoiesis or ablating HSC proliferation capacity, dependent on the context. Mechanistically, low doses of the CKS1 inhibitor (CKS1i) activates Foxo1 signalling potentiating B-cell differentiation, but impairing HSC proliferation. These results reveal a novel role for the SCF-CKS1 complex in boosting haematopoiesis and propose the use of rapid ex vivo models to investigate the long-term effects of chemotherapeutic treatments targeting HSCs with the potential of reducing late adverse effects.

U2 - 10.1016/j.exphem.2025.104768

DO - 10.1016/j.exphem.2025.104768

M3 - Article

C2 - 40164326

SN - 0301-472X

VL - 146

JO - Experimental hematology

JF - Experimental hematology

M1 - 104768

ER -