PDF(Pubmed)
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.
摘要：
针对BCR的酪氨酸激酶抑制剂（TKIs）：ABL1已将慢性髓性白血病（CML）从致命疾病转变为大多数患者的可控制疾病。尽管生存率提高了,靶向耐药白血病干细胞(LSCs)仍然是治愈性CML治疗的挑战.异常的脂质代谢可以对膜动力学产生很大的影响，癌症中的细胞存活和治疗反应。虽然神经酰胺和鞘脂水平先前与CML中的TKI反应相关，脂质代谢在TKI耐药中的作用尚不清楚。我们已经确定了脂质代谢的关键调节剂的下调，G0/G1转换基因2（G0S2），在TKI抵抗的多个场景中，包括(1)BCR::ABL1激酶非依赖性TKI抗性，(2)CML从慢性期进展到疾病的爆发期,和（3）在CML与正常骨髓祖细胞中。因此，G0S2表达水平低的CML患者的总体生存率较差。CML中的G0S2下调不是启动子高甲基化或BCR::ABL1激酶活性的结果，而是由于MYC的转录抑制。使用CML细胞系，患者样本和G0s2敲除（G0s2-/-）小鼠，我们证明了G0S2在CML和TKI耐药中的肿瘤抑制作用。我们的数据表明，CML中G0S2蛋白表达降低会破坏甘油磷脂代谢，与使CML细胞对治疗产生抗性的分化阻滞相关。总之,我们的数据揭示了G0S2在调节CML中髓样分化和TKI反应中的新作用，并建议恢复G0S2可能具有临床实用性。
