Role of cardiolipins, mitochondria, and autophagy in the differentiation process activated by all-trans retinoic acid in acute promyelocytic leukemia.
Role of cardiolipins, mitochondria, and autophagy in the differentiation process activated by all-trans retinoic acid in acute promyelocytic leukemia.
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DOI：
10.1038/s41419-021-04476-z
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发表时间：
2022-01-10
影响因子：
9
通讯作者：
Garattini E
中科院分区：
文献类型：
--
作者：
Gianni' M;Goracci L;Schlaefli A;Di Veroli A;Kurosaki M;Guarrera L;Bolis M;Foglia M;Lupi M;Tschan MP;Cruciani G;Terao M;Garattini E
在急性早幼粒细胞白血病（APL）原始细胞中，脂质在全反式维甲酸（ATRA）激活的粒细胞分化过程中所起的作用尚不清楚。NB 4细胞株可再现ATRA激活APL原始细胞的粒细胞分化过程，其特征是表达致病性PML-RARα融合蛋白。在本研究中，我们使用NB 4模型来定义ATRA对脂质稳态的影响。使用高通量lipidomic的方法，我们证明，暴露的APL-衍生的NB 4细胞系ATRA导致心磷脂，线粒体膜的主要脂质成分的量的早期减少。心磷脂水平的降低导致线粒体活性的伴随抑制。这些ATRA依赖性作用与粒细胞成熟过程有因果关系。事实上，ATRA诱导的心磷脂减少和伴随的线粒体功能障碍先于类维生素A敏感的NB 4细胞的分化，而这两种现象在类维生素A抗性的NB 4.306对应物中未观察到。此外，乙醇胺诱导的心磷脂缺乏激活的线粒体功能障碍的救援抑制ATRA依赖性粒细胞分化和诱导相关的自噬过程。在亲本NB 4细胞和NB 4衍生的细胞群体中进行的RNA-seq研究，其特征在于自噬介体ATG 5的沉默，提供了对ATRA分化作用的潜在机制的见解。结果表明，ATRA导致显着下调CRLS 1（心磷脂合成酶-1）和LPCAT 1（溶血磷脂酰胆碱酰基转移酶-1）的mRNA，这两种酶催化心磷脂合成的最后一步。CRLS 1和LPCAT 1 mRNA的ATRA依赖性下调在功能上是相关的，因为它伴随着相应蛋白质的量的显著减少。此外，CRLS 1和LPCAT 1水平的降低需要自噬过程的激活，因为这两种蛋白质的下调在ATG 5沉默的NB 4-shATG 5细胞中被阻断。
The role played by lipids in the process of granulocytic differentiation activated by all-trans retinoic acid (ATRA) in Acute-Promyelocytic-Leukemia (APL) blasts is unknown. The process of granulocytic differentiation activated by ATRA in APL blasts is recapitulated in the NB4 cell-line, which is characterized by expression of the pathogenic PML-RARα fusion protein. In the present study, we used the NB4 model to define the effects exerted by ATRA on lipid homeostasis. Using a high-throughput lipidomic approach, we demonstrate that exposure of the APL-derived NB4 cell-line to ATRA causes an early reduction in the amounts of cardiolipins, a major lipid component of the mitochondrial membranes. The decrease in the levels of cardiolipins results in a concomitant inhibition of mitochondrial activity. These ATRA-dependent effects are causally involved in the granulocytic maturation process. In fact, the ATRA-induced decrease of cardiolipins and the concomitant dysfunction of mitochondria precede the differentiation of retinoid-sensitive NB4 cells and the two phenomena are not observed in the retinoid-resistant NB4.306 counterparts. In addition, ethanolamine induced rescue of the mitochondrial dysfunction activated by cardiolipin deficiency inhibits ATRA-dependent granulocytic differentiation and induction of the associated autophagic process. The RNA-seq studies performed in parental NB4 cells and a NB4-derived cell population, characterized by silencing of the autophagy mediator, ATG5, provide insights into the mechanisms underlying the differentiating action of ATRA. The results indicate that ATRA causes a significant down-regulation of CRLS1 (Cardiolipin-synthase-1) and LPCAT1 (Lysophosphatidylcholine-Acyltransferase-1) mRNAs which code for two enzymes catalyzing the last steps of cardiolipin synthesis. ATRA-dependent down-regulation of CRLS1 and LPCAT1 mRNAs is functionally relevant, as it is accompanied by a significant decrease in the amounts of the corresponding proteins. Furthermore, the decrease in CRLS1 and LPCAT1 levels requires activation of the autophagic process, as down-regulation of the two proteins is blocked in ATG5-silenced NB4-shATG5 cells.
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