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

Abstract

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.

The acquisition order of leukemic drug resistance mutations is directed by the selective fitness associated with each resistance mechanism

“…SPP1 (encoding osteopontin) 31 , 32 , MAPK4 33 , SMO (encoding smoothened) 34 , 35 and FZD3 (encoding frizzled protein 3) 36 have known function as cancer progression promoters. Furthermore, there was down-regulation of tumor suppressor gene RBM47 37 , and the apoptotic regulator, G0S2 38 , 39 .…”

“…Furthermore, reduced expression of the G0S2 switch gene was observed in early stage resistant cells compared with control. The protein product of G0S2 canonically interacts with the apoptotic Bcl2 protein, which may have allowed a protective lowering of apoptosis 38 , 39 , 70 . G0S2 activity also results in a differentiation block and TKI resistance in CML cells 39 .…”

Bone marrow adipocyte: Origin, biology and relationship with hematological malignancy

“…Antidiabetic drugs, such as pioglitazone, bisbiguanide Alexidine (ALX), strongly cooperate with front-line therapies, promoting myeloid differentiation and decreasing the infiltration of LSC pool through stimulating transcription of CEBPβ and PPARγ. 59 As for the target therapy about lipid metabolism, it is suggested that FAO inhibitors (such as Avocatin B) can block energy support and induce an integrated stress response with high ROS formation, exerting synergistic effect with current chemotherapeutic drugs in AML. 56 BMAds also secret elevated asparagine and glutamine in ALL, inhibiting the L-asparaginase (ASNase)-induced toxicity.…”

“…In recent years, the importance of lipid homeostasis in LSC‐target therapy attracts increasing attention. Antidiabetic drugs, such as pioglitazone, bis‐biguanide Alexidine (ALX), strongly cooperate with front‐line therapies, promoting myeloid differentiation and decreasing the infiltration of LSC pool through stimulating transcription of CEBPβ and PPARγ 59 …”

Variation in Lipid Species Profiles among Leukemic Cells Significantly Impacts Their Sensitivity to the Drug Targeting of Lipid Metabolism and the Prognosis of AML Patients

“…This particular role of FAO in the survival of leukemic cells was also underlined in a demonstration of the overexpression of the enzyme 3-very long chain acyl-CoA dehydrogenase (VLCAD) in AML, of which a decrease in proliferation can be induced by gene attenuation or pharmacological inhibition via alteration of the Krebs cycle [ 4 ]. Additionally, a recent study demonstrated that glycerophospholipid metabolism is involved in drug resistance in chronic myeloid leukemia through downregulation of the G0/G1 switch gene 2 (G0S2), which confers worse overall survival to patients [ 5 ]. Similarly, Carnitine Palmitoyltransferase 1A (CPT1A), a key enzyme in carnitine-dependent transport across the mitochondrial inner membrane of FAs, was found to be overexpressed in bone marrow samples from AML patients with poor prognosis compared to those with normal bone marrow [ 6 ].…”