Department of Internal Medicine, American University of Beirut, Beirut, Lebanon; Department of Anatomy, Cell Biology and Physiological Sciences, American University of Beirut, Beirut, Lebanon.
Department of Experimental Pathology, Microbiology and Immunology, Beirut.
Haematologica. 2021 Dec 1;106(12):3090-3099. doi: 10.3324/haematol.2020.274878.
Retinoic acid (RA) was proposed to increase survival of chemotherapy- treated patients with nucleophosmin-1 (NPM-1c)-mutated acute myeloid leukemia. We reported that, ex vivo, RA triggers NPM-1c degradation, P53 activation and growth arrest. PML organizes domains that control senescence or proteolysis. Here, we demonstrate that PML is required to initiate RA-driven NPM-1c degradation, P53 activation and cell death. Mechanistically, RA enhances PML basal expression through inhibition of activated Pin1, prior to NPM-1c degradation. Such PML induction drives P53 activation, favoring blast response to chemotherapy or arsenic in vivo. This RA/PML/P53 cascade could mechanistically explain RA-facilitated chemotherapy response in patients with NPM-1c mutated acute myeloid leukemia.
维甲酸（RA）被提议用于提高核磷蛋白 1（NPM-1c）突变急性髓系白血病患者经化疗治疗后的存活率。我们曾报道，RA 可在体外触发 NPM-1c 降解、P53 激活和细胞生长停滞。PML 组织控制衰老或蛋白水解的域。在此，我们证明 PML 对于启动 RA 驱动的 NPM-1c 降解、P53 激活和细胞死亡是必需的。从机制上讲，RA 通过抑制活化的 Pin1 增强 PML 的基础表达，然后才降解 NPM-1c。这种 PML 诱导驱动 P53 激活，有利于体内化疗或砷对白血病细胞的杀伤作用。这种 RA/PML/P53 级联反应可以从机制上解释 RA 促进 NPM-1c 突变急性髓系白血病患者化疗反应的原因。
