Hou Wen, Wang Zhen-Ya, Lin Jing, Chen Wei-Min
International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE), College of Pharmacy, Jinan University, Guangzhou, 510632, PR China.
Cell Death Discov. 2020 Nov 12;6(1):123. doi: 10.1038/s41420-020-00354-3.
Differentiation therapy has been successfully applied clinically in cases of acute promyelocytic leukemia (APL), but few differentiation-induction agents other than all-trans retinoic acid (ATRA) have been discovered clinically. Based on our previously reported neuritogenic differentiation activity of synthetic dimeric derivatives of securinine, we explored the leukemia differentiation-induction activity of such as compound, SN3-L6. It was found that SN3-L6 induces transdifferentiation of both acute myeloid leukemia (AML) and chronic myelogenous leukemia (CML) cells but unexpectedly, a new transdifferentiation pathway from APL cells to morphologically and immunologically normal megakaryocytes and platelets were discovered. SN3-L6 fails to induce transdifferentiation of ATRA-produced mature granulocytes into megakaryocytes, indicating its selectivity between mature and immature cells. SN3-L6 induces CML K562 cells to transdifferentiate into apoptotic megakaryocytes but without platelet formation, indicating a desirable selectivity between different leukemia cells. Our data illuminate a differentiation gap between AML cells and platelets, and promises applications in leukemia differentiation therapy strategy.
分化疗法已在急性早幼粒细胞白血病（APL）病例中成功应用于临床，但除全反式维甲酸（ATRA）外，临床上发现的分化诱导剂很少。基于我们之前报道的一叶萩碱合成二聚体衍生物的促神经突分化活性，我们探索了此类化合物SN3-L6的白血病分化诱导活性。结果发现，SN3-L6可诱导急性髓系白血病（AML）和慢性粒细胞白血病（CML）细胞转分化，但出乎意料的是，发现了一条从APL细胞到形态和免疫正常的巨核细胞和血小板的新转分化途径。SN3-L6无法诱导ATRA产生的成熟粒细胞转分化为巨核细胞，表明其在成熟细胞和未成熟细胞之间具有选择性。SN3-L6诱导CML K562细胞转分化为凋亡性巨核细胞，但无血小板形成，表明其在不同白血病细胞之间具有理想的选择性。我们的数据揭示了AML细胞与血小板之间的分化差距，并有望应用于白血病分化治疗策略。
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