Ramirez-Guzman, Lizbeth A. and Huang, Wenjing and Cole, John J. and Jorgensen, Heather G. (2024) GAS2 upregulation is a targetable vulnerability in chronic myeloid leukaemia. International Journal of Translational Medicine, 4 (2). pp. 354-368. ISSN 2673-8937
AI Summary:
The study investigates potentially tractable vulnerabilities in chronic myeloid leukemia (CML) leukemia stem cells (LSCs). The researchers found that GAS2 is significantly upregulated in CML LSCs and propose using XK469, a topoisomerase II inhibitor, as a candidate small-molecule inhibitor of GAS2.AI Topics:
Tyrosine kinase inhibitors (TKIs), such as imatinib (IM), increase the survival of chronic myeloid leukemia (CML) patients but do not eradicate the disease as leukemia stem cells (LSCs) with primitive and quiescent signatures persist after TKI monotherapy, driving disease relapse. Using single-cell publicly available transcriptomic data, we investigated potentially tractable vulnerabilities in this persistent CML LSC population. GAS2 is significantly upregulated when comparing LSCs from CML patients in remission to normal hematopoietic stem cells (HSCs). A topoisomerase IIβ inhibitor, XK469, was proposed to be repurposed as a candidate small-molecule inhibitor of GAS2, and its effect was investigated in cell line models in combination with IM in vitro. Alone, XK469 could induce cell cycle arrest/differentiation in CML cells and reduce cell viability. In combination with IM, XK469 significantly increased CML cell apoptosis and reduced CML cell clonogenic capacity. These results suggest that GAS2 is a targetable vulnerability in CML LSCs and that using XK469 in combination with TKI potentiates the sensitivity of CML cells to IM.
Ramirez-Guzman, Lizbeth A.
Author
Ramirez-Guzman, Lizbeth A. and Huang, Wenjing and Cole, John J. and Jorgensen, Heather G. (2024) GAS2 upregulation is a targetable vulnerability in chronic myeloid leukaemia. International Journal of Translational Medicine, 4 (2). pp. 354-368. ISSN 2673-8937
See full publications listHuang, Wenjing
Author
Ramirez-Guzman, Lizbeth A. and Huang, Wenjing and Cole, John J. and Jorgensen, Heather G. (2024) GAS2 upregulation is a targetable vulnerability in chronic myeloid leukaemia. International Journal of Translational Medicine, 4 (2). pp. 354-368. ISSN 2673-8937
See full publications listCole, John
Author
Ramirez-Guzman, Lizbeth A. and Huang, Wenjing and Cole, John J. and Jorgensen, Heather G. (2024) GAS2 upregulation is a targetable vulnerability in chronic myeloid leukaemia. International Journal of Translational Medicine, 4 (2). pp. 354-368. ISSN 2673-8937
Nair, Reshmi and Lannagan, Tamsin R.M. and Jackstadt, Rene and Andrusaite, Anna and Cole, John and Boyne, Caitlin and Nibbs, Robert J.B. and Sansom, Owen J. and Milling, Simon (2024) Co-inhibition of TGF-β and PD-L1 pathways in a metastatic colorectal cancer mouse model triggers interferon responses, innate cells and T cells, alongside metabolic changes and tumor resistance. OncoImmunology, 13 (1): 2330194. ISSN 2162-4011
See full publications listJorgensen, Heather G.
Author
Patterson, Shaun D. and Massett, Matthew E. and Huang, Xu and Jørgensen, Heather G. and Michie, Alison M. (2024) The MYC–NFATC2 axis maintains the cell cycle and mitochondrial function in acute myeloid leukaemia cells. Molecular Oncology, 18 (9). pp. 2234-2254. ISSN 1574-7891
Ramirez-Guzman, Lizbeth A. and Huang, Wenjing and Cole, John J. and Jorgensen, Heather G. (2024) GAS2 upregulation is a targetable vulnerability in chronic myeloid leukaemia. International Journal of Translational Medicine, 4 (2). pp. 354-368. ISSN 2673-8937
Scott, Mary T. and Liu, Wei and Mitchell, Rebecca and Clarke, Cassie J. and Kinstrie, Ross and Warren, Felix and Almasoudi, Hassan and Stevens, Thomas and Dunn, Karen and Pritchard, John and Drotar, Mark E. and Michie, Alison M. and Jorgensen, Heather G. and Higgins, Brian and Copland, Mhairi and Vetrie, David (2024) Activating p53 abolishes self-renewal of quiescent leukaemic stem cells in residual CML disease. Nature Communications, 15: 651. ISSN 2041-1723
See full publications listAvailable under License Creative Commons Attribution.
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