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

• Published in: Clinical and translational medicine Vol. 12; no. 12; pp. e1146 - n/a
• Main Authors: Gonzalez, Mayra A., Olivas, Idaly M., Bencomo‐Alvarez, Alfonso E., Rubio, Andres J., Barreto‐Vargas, Christian, Lopez, Jose L., Dang, Sara K., Solecki, Jonathan P., McCall, Emily, Astudillo, Gonzalo, Velazquez, Vanessa V., Schenkel, Katherine, Reffell, Kelaiah, Perkins, Mariah, Nguyen, Nhu, Apaflo, Jehu N., Alvidrez, Efren, Young, James E., Lara, Joshua J., Yan, Dongqing, Senina, Anna, Ahmann, Jonathan, Varley, Katherine E., Mason, Clinton C., Eide, Christopher A., Druker, Brian J., Nurunnabi, Md, Padilla, Osvaldo, Bajpeyi, Sudip, Eiring, Anna M.
• Format: Journal Article
• Language: English
• Published: United States John Wiley & Sons, Inc 01-12-2022; John Wiley and Sons Inc; Wiley
• Subjects: Animals; Apoptosis; Cell Cycle Proteins - genetics; chronic myeloid leukaemia (CML); Clinical medicine; Cytokines; Disease Progression; Drug resistance; Drug Resistance, Neoplasm - genetics; Flow cytometry; Fusion Proteins, bcr-abl - genetics; G0/G1 switch gene 2 (G0S2); Genes, Switch; glycerophospholipid metabolism; Glycerophospholipids - metabolism; Granulocytes; Health sciences; Humans; Kinases; Laboratories; Leukemia; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - genetics; Ligands; Mice; Patients; Penicillin; Polymerase chain reaction; Protein Kinase Inhibitors - therapeutic use; Stem cells; tyrosine kinase inhibitor (TKI) resistance; United States > US; G0/G1 switch gene 2 (G0S2); chronic myeloid leukaemia (CML); tyrosine kinase inhibitor (TKI) resistance; glycerophospholipid metabolism
• ISSN: 2001-1326; 2001-1326
• DOI: 10.1002/ctm2.1146

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.
G0S2 is reduced in disease progression and drug resistance of CML.
G0S2 expression impairs survival of CML progenitors with little effect on apoptosis.
G0S2 function in CML is independent of its known function as an inhibitor of adipose triglyceride lipase (ATGL), the rate‐limiting enzyme for intracellular lipolysis.
Loss of G0S2 disrupts glycerophospholipid metabolism in CML and promotes therapy resistance.