MacDonald Robert J, Bunaciu Rodica P, Ip Victoria, Dai David, Tran David, Varner Jeffrey D, Yen Andrew
a Department of Biomedical Sciences , Cornell University , Ithaca , NY , USA.
b Robert Frederick Smith School of Chemical and Biomolecular Engineering , Cornell University , Ithaca , NY , USA.
Leuk Lymphoma. 2018 Dec;59(12):2941-2951. doi: 10.1080/10428194.2018.1452213. Epub 2018 Mar 23.
The acute promyelocytic leukemia (APL) has been treated with all-trans retinoic acid (RA) for decades. While RA has largely been ineffective in non-APL AML subtypes, co-treatments combining RA and other agents are currently in clinical trials. Using the RA-responsive non-APL AML cell line HL-60, we tested the efficacy of the Src family kinase (SFK) inhibitor bosutinib on RA-induced differentiation. HL-60 has been recently shown to bear fidelity to a subtype of AML that respond to RA. We found that co-treatment with RA and bosutinib enhanced differentiation evidenced by increased CD11b expression, G/G cell cycle arrest, and respiratory burst. Expression of the SFK members Fgr and Lyn was enhanced, while SFK activation was inhibited. Phosphorylation of several sites of c-Raf was increased and expression of AhR and p85 PI3K was enhanced. Expression of c-Cbl and mTOR was decreased. Our study suggests that SFK inhibition enhances RA-induced differentiation and may have therapeutic value in non-APL AML.
急性早幼粒细胞白血病（APL）使用全反式维甲酸（RA）治疗已有数十年。虽然RA在非APL急性髓系白血病（AML）亚型中大多无效，但目前RA与其他药物联合治疗正处于临床试验阶段。我们使用对RA有反应的非APL AML细胞系HL-60，测试了Src家族激酶（SFK）抑制剂博舒替尼对RA诱导分化的疗效。最近研究表明HL-60与对RA有反应的一种AML亚型具有一致性。我们发现，RA与博舒替尼联合治疗可增强分化，表现为CD11b表达增加、G/G细胞周期阻滞和呼吸爆发。SFK成员Fgr和Lyn的表达增强，而SFK激活受到抑制。c-Raf多个位点的磷酸化增加，芳烃受体（AhR）和p85磷脂酰肌醇-3激酶（PI3K）的表达增强。c-Cbl和雷帕霉素靶蛋白（mTOR）的表达降低。我们的研究表明，抑制SFK可增强RA诱导的分化，可能对非APL AML具有治疗价值。
