Loss of G0/G1 switch gene 2 (G0S2) promotes disease progression and drug resistance in chronic myeloid leukaemia (CML) by disrupting glycerophospholipid metabolism.

Autor: Gonzalez MA; Department of Molecular and Translational Medicine, Center of Emphasis in Cancer, Texas Tech University Health Sciences Center El Paso, El Paso, Texas, USA., Olivas IM; Department of Molecular and Translational Medicine, Center of Emphasis in Cancer, Texas Tech University Health Sciences Center El Paso, El Paso, Texas, USA.; L. Frederick Francis Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center El Paso, El Paso, Texas, USA., Bencomo-Alvarez AE; Department of Molecular and Translational Medicine, Center of Emphasis in Cancer, Texas Tech University Health Sciences Center El Paso, El Paso, Texas, USA., Rubio AJ; Department of Molecular and Translational Medicine, Center of Emphasis in Cancer, Texas Tech University Health Sciences Center El Paso, El Paso, Texas, USA.; Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center El Paso, El Paso, Texas, USA., Barreto-Vargas C; Immunology Division, University of Guadalajara, Guadalajara, Jalisco, Mexico., Lopez JL; Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center El Paso, El Paso, Texas, USA., Dang SK; L. Frederick Francis Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center El Paso, El Paso, Texas, USA.; Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center El Paso, El Paso, Texas, USA., Solecki JP; L. Frederick Francis Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center El Paso, El Paso, Texas, USA., McCall E; Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center El Paso, El Paso, Texas, USA., Astudillo G; Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center El Paso, El Paso, Texas, USA., Velazquez VV; Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center El Paso, El Paso, Texas, USA., Schenkel K; Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center El Paso, El Paso, Texas, USA., Reffell K; L. Frederick Francis Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center El Paso, El Paso, Texas, USA., Perkins M; Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center El Paso, El Paso, Texas, USA., Nguyen N; Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center El Paso, El Paso, Texas, USA., Apaflo JN; Metabolic, Nutrition and Exercise Research (MiNER) Laboratory, Department of Kinesiology, University of Texas at El Paso, El Paso, Texas, USA., Alvidrez E; Department of Pharmaceutical Sciences, School of Pharmacy, University of Texas at El Paso, El Paso, Texas, USA., Young JE; L. Frederick Francis Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center El Paso, El Paso, Texas, USA., Lara JJ; L. Frederick Francis Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center El Paso, El Paso, Texas, USA.; Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center El Paso, El Paso, Texas, USA., Yan D; Huntsman Cancer Institute, The University of Utah, Salt Lake City, Utah, USA., Senina A; Huntsman Cancer Institute, The University of Utah, Salt Lake City, Utah, USA., Ahmann J; Huntsman Cancer Institute, The University of Utah, Salt Lake City, Utah, USA., Varley KE; Huntsman Cancer Institute, The University of Utah, Salt Lake City, Utah, USA., Mason CC; Huntsman Cancer Institute, The University of Utah, Salt Lake City, Utah, USA., Eide CA; Knight Cancer Institute, Division of Hematology/Medical Oncology, Oregon Health & Science University, Portland, Oregon, USA., Druker BJ; Knight Cancer Institute, Division of Hematology/Medical Oncology, Oregon Health & Science University, Portland, Oregon, USA., Nurunnabi M; Department of Pharmaceutical Sciences, School of Pharmacy, University of Texas at El Paso, El Paso, Texas, USA., Padilla O; Department of Pathology, Texas Tech University Health Sciences Center El Paso, El Paso, Texas, USA., Bajpeyi S; Metabolic, Nutrition and Exercise Research (MiNER) Laboratory, Department of Kinesiology, University of Texas at El Paso, El Paso, Texas, USA., Eiring AM; Department of Molecular and Translational Medicine, Center of Emphasis in Cancer, Texas Tech University Health Sciences Center El Paso, El Paso, Texas, USA.; L. Frederick Francis Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center El Paso, El Paso, Texas, USA.; Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center El Paso, El Paso, Texas, USA.
Jazyk: angličtina
Zdroj: Clinical and translational medicine [Clin Transl Med] 2022 Dec; Vol. 12 (12), pp. e1146.
DOI: 10.1002/ctm2.1146
Abstrakt: Tyrosine kinase inhibitors (TKIs) targeting BCR::ABL1 have turned chronic myeloid leukaemia (CML) from a fatal disease into a manageable condition for most patients. Despite improved survival, targeting drug-resistant leukaemia stem cells (LSCs) remains a challenge for curative CML therapy. Aberrant lipid metabolism can have a large impact on membrane dynamics, cell survival and therapeutic responses in cancer. While ceramide and sphingolipid levels were previously correlated with TKI response in CML, the role of lipid metabolism in TKI resistance is not well understood. We have identified downregulation of a critical regulator of lipid metabolism, G0/G1 switch gene 2 (G0S2), in multiple scenarios of TKI resistance, including (1) BCR::ABL1 kinase-independent TKI resistance, (2) progression of CML from the chronic to the blast phase of the disease, and (3) in CML versus normal myeloid progenitors. Accordingly, CML patients with low G0S2 expression levels had a worse overall survival. G0S2 downregulation in CML was not a result of promoter hypermethylation or BCR::ABL1 kinase activity, but was rather due to transcriptional repression by MYC. Using CML cell lines, patient samples and G0s2 knockout (G0s2 -/- ) mice, we demonstrate a tumour suppressor role for G0S2 in CML and TKI resistance. Our data suggest that reduced G0S2 protein expression in CML disrupts glycerophospholipid metabolism, correlating with a block of differentiation that renders CML cells resistant to therapy. Altogether, our data unravel a new role for G0S2 in regulating myeloid differentiation and TKI response in CML, and suggest that restoring G0S2 may have clinical utility.
(© 2022 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.)
Databáze: MEDLINE
Externí odkaz:
Nepřihlášeným uživatelům se plný text nezobrazuje