Panuzzo Cristina, Signorino Elisabetta, Calabrese Chiara, Ali Muhammad Shahzad, Petiti Jessica, Bracco Enrico, Cilloni Daniela
Department of Clinical and Biological Sciences, University of Turin, 10124 Turin, Italy.
Department of Oncology, University of Turin, 10124 Turin, Italy.
J Clin Med. 2020 Mar 16;9(3):802. doi: 10.3390/jcm9030802.
Acute myeloid leukemia is mainly characterized by a complex and dynamic genomic instability. Next-generation sequencing has significantly improved the ability of diagnostic research to molecularly characterize and stratify patients. This detailed outcome allowed the discovery of new therapeutic targets and predictive biomarkers, which led to develop novel compounds (e.g., IDH 1 and 2 inhibitors), nowadays commonly used for the treatment of adult relapsed or refractory AML. In this review we summarize the most relevant mutations affecting tumor suppressor genes that contribute to the onset and progression of AML pathology. Epigenetic modifications (TET2, IDH1 and IDH2, DNMT3A, ASXL1, WT1, EZH2), DNA repair dysregulation (TP53, NPM1), cell cycle inhibition and deficiency in differentiation (NPM1, CEBPA, TP53 and GATA2) as a consequence of somatic mutations come out as key elements in acute myeloid leukemia and may contribute to relapse and resistance to therapies. Moreover, spliceosomal machinery mutations identified in the last years, even if in a small cohort of acute myeloid leukemia patients, suggested a new opportunity to exploit therapeutically. Targeting these cellular markers will be the main challenge in the near future in an attempt to eradicate leukemia stem cells.
急性髓系白血病主要特征为复杂且动态的基因组不稳定性。下一代测序显著提高了诊断研究对患者进行分子特征分析和分层的能力。这一详细结果促使发现了新的治疗靶点和预测性生物标志物，进而推动开发了新型化合物（如异柠檬酸脱氢酶1和2抑制剂），如今这些化合物常用于治疗成人复发或难治性急性髓系白血病。在本综述中，我们总结了影响肿瘤抑制基因的最相关突变，这些突变促成了急性髓系白血病病理的发生和进展。由于体细胞突变导致的表观遗传修饰（TET2、异柠檬酸脱氢酶1和2、DNA甲基转移酶3A、ASXL1、WT1、EZH2）、DNA修复失调（TP53、核仁磷酸蛋白1）、细胞周期抑制和分化缺陷（核仁磷酸蛋白1、CCAAT增强子结合蛋白α、TP53和GATA2）成为急性髓系白血病的关键因素，并可能导致复发和对治疗产生耐药性。此外，近年来在一小部分急性髓系白血病患者中发现的剪接体机制突变提示了一个新的治疗开发机会。在不久的将来，靶向这些细胞标志物将是根除白血病干细胞的主要挑战。
