van Gils Noortje, Verhagen Han J M P, Smit Linda
Department of Hematology, VU University Medical Center, Cancer Center Amsterdam, Amsterdam, The Netherlands.
Department of Hematology, VU University Medical Center, Cancer Center Amsterdam, Amsterdam, The Netherlands.
Exp Hematol. 2017 Aug;52:12-23. doi: 10.1016/j.exphem.2017.04.007. Epub 2017 Apr 27.
The success of all-trans retinoic acid (ATRA) therapy for acute promyelocytic leukemia (APL) provides a rationale for using retinoic acid (RA)-based therapy for other subtypes of acute myeloid leukemia (AML). Recently, several studies showed that ATRA may drive leukemic cells efficiently into differentiation and/or apoptosis in a subset of AML patients with an NPM1 mutation, a FLT3-ITD, an IDH1 mutation, and patients overexpressing EVI-1. Because not all patients within these molecular subgroups respond to ATRA and clinical trials that tested ATRA response in non-APL AML patients have had disappointing results, the identification of additional biomarkers may help to identify patients who strongly respond to ATRA-based therapy. Searching for response biomarkers might also reveal novel RA-based combination therapies with an efficient differentiation/apoptosis-inducing effect in non-APL AML patients. Preliminary studies suggest that the epigenetic or transcriptional state of leukemia cells determines their susceptibility to ATRA. We hypothesize that reprogramming by inhibitors of epigenetic-modifying enzymes or by modulation of microRNA expression might sensitize non-APL AML cells for RA-based therapy. AML relapse is caused by a subpopulation of leukemia cells, named leukemic stem cells (LSCs), which are in a different epigenetic state than the total bulk of the AML. The survival of LSCs after therapy is the main cause of the poor prognosis of AML patients, and novel differentiation therapies should drive these LSCs into maturity. In this review, we summarize the current knowledge on the epigenetic aspects of susceptibility to RA-induced differentiation in APL and non-APL AML.
全反式维甲酸（ATRA）治疗急性早幼粒细胞白血病（APL）的成功为基于维甲酸（RA）的疗法用于急性髓系白血病（AML）的其他亚型提供了理论依据。最近，多项研究表明，ATRA可能会有效地促使一部分伴有NPM1突变、FLT3内部串联重复突变（FLT3-ITD）、异柠檬酸脱氢酶1（IDH1）突变的AML患者以及过表达EVI-1的患者的白血病细胞发生分化和/或凋亡。由于并非这些分子亚组中的所有患者都对ATRA有反应，并且在非APL AML患者中测试ATRA反应的临床试验结果令人失望，因此识别其他生物标志物可能有助于确定对基于ATRA的疗法有强烈反应的患者。寻找反应性生物标志物也可能揭示在非APL AML患者中具有有效诱导分化/凋亡作用的新型基于RA的联合疗法。初步研究表明，白血病细胞的表观遗传或转录状态决定了它们对ATRA的敏感性。我们假设，通过表观遗传修饰酶抑制剂进行重编程或通过调节微小RNA表达可能会使非APL AML细胞对基于RA的疗法敏感。AML复发是由一群名为白血病干细胞（LSCs）的白血病细胞亚群引起的，这些细胞的表观遗传状态与AML的总体细胞不同。治疗后LSCs的存活是AML患者预后不良的主要原因，新型分化疗法应促使这些LSCs成熟。在这篇综述中，我们总结了目前关于APL和非APL AML中对RA诱导分化敏感性的表观遗传方面的知识。
