Moretti Simona, Abdel-Aziz Amal Kamal, Ceccacci Elena, Pallavicini Isabella, Santoro Fabio, de Thé Hugues, Minucci Saverio
Department of Experimental Oncology, European Institute of Oncology IRCCS, Milan, Italy.
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt.
Leukemia. 2022 May;36(5):1306-1312. doi: 10.1038/s41375-022-01530-3. Epub 2022 Mar 4.
According to a hierarchical model, targeting leukemia-initiating cells (LICs) was speculated to achieve complete remission (CR) or cure. Nonetheless, increasing evidence emphasized the plasticity of differentiated blasts undergoing interconversion into LICs. We exploited murine models of acute promyelocytic leukemia (APL), a subtype of acute myeloid leukemia driven by the promyelocytic leukemia/retinoic acid receptor (PML-RARα) oncofusion protein, which recruits histone deacetylase (HDAC)-containing complexes. We studied APLs with different LIC frequencies and investigated the effect of two HDAC inhibitors: valproic acid (VPA), with relative selectivity towards class I HDAC enzymes and vorinostat/suberoylanilide hydroxamic acid (SAHA) (pan-HDAC inhibitor) in combination with all-trans retinoic acid (ATRA), on the bulk APL cells and APL LICs. Indeed, we found that while VPA differentiates the bulk APL cells, SAHA selectively targets LICs. ATRA + VPA + SAHA combination efficiently induced CR in an APL model with lower LIC frequency. Substituting ATRA with synthetic retinoids as etretinate which promotes APL differentiation without downregulating PML/RARα compromised the therapeutic benefit of ATRA + VPA + SAHA regimen. Altogether, our study emphasizes the therapeutic power of co-targeting the plasticity and heterogeneity of cancer -herein demonstrated by tackling LICs and bulk leukemic blasts - to achieve and maintain CR.
根据一种分层模型，推测靶向白血病起始细胞（LICs）可实现完全缓解（CR）或治愈。然而，越来越多的证据强调了分化的原始细胞向LICs相互转化的可塑性。我们利用急性早幼粒细胞白血病（APL）的小鼠模型，APL是急性髓系白血病的一种亚型，由早幼粒细胞白血病/维甲酸受体（PML-RARα）致癌融合蛋白驱动，该蛋白募集含组蛋白脱乙酰酶（HDAC）的复合物。我们研究了具有不同LIC频率的APL，并研究了两种HDAC抑制剂：对I类HDAC酶具有相对选择性的丙戊酸（VPA）和伏立诺他/辛二酰苯胺异羟肟酸（SAHA）（泛HDAC抑制剂）与全反式维甲酸（ATRA）联合使用，对大量APL细胞和APL LICs的影响。事实上，我们发现，虽然VPA可使大量APL细胞分化，但SAHA选择性地靶向LICs。ATRA + VPA + SAHA联合用药在LIC频率较低的APL模型中有效诱导CR。用合成维甲酸如依曲替酯替代ATRA，依曲替酯可促进APL分化而不降低PML/RARα，这损害了ATRA + VPA + SAHA方案的治疗效果。总之，我们的研究强调了共同靶向癌症可塑性和异质性的治疗能力——在此通过处理LICs和大量白血病原始细胞得以证明——以实现和维持CR。
