Lamba Jatinder K, Cao Xueyuan, Raimondi Susana, Downing James, Ribeiro Raul, Gruber Tanja A, Rubnitz Jeffrey, Pounds Stanley
Department of Pharmacotherapy and Translational Research, College of Pharmacy, University of Florida, Gainesville, FL 32608, USA.
Department of Acute and Tertiary Care, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
Cancers (Basel). 2020 Oct 17;12(10):3024. doi: 10.3390/cancers12103024.
Acute Myeloid Leukemia (AML) is characterized by recurrent genetic and cytogenetic lesions that are utilized for risk stratification and for making treatment decisions. In recent years, methylation dysregulation has been extensively studied and associated with risk groups and prognosis in adult AML, however, such studies in pediatric AML are limited. Moreover, the mutations in epigenetic genes such as , or are almost absent or rare in pediatric patients as compared to their abundance in adult AML. In the current study, we evaluated methylation patterns that occur with or independent of the well-defined cytogenetic features in pediatric AML patients enrolled on multi-site AML02 clinical trial (NCT00136084). Our results demonstrate that unlike adult AML, cytosine DNA methylation does not result in significant unique clusters in pediatric AML, however, DNA methylation signatures correlated significantly with the most common and recurrent cytogenetic features. Paired evaluation of DNA methylation and expression identified genes and pathways of biological relevance that hold promise for novel therapeutic strategies. Our results further demonstrate that epigenetic signatures occur complimentary to the well-established chromosomal/mutational landscape, implying that dysregulation of oncogenes or tumor suppressors might be leveraging both genetic and epigenetic mechanisms to impact biological pathways critical for leukemogenesis.
急性髓系白血病（AML）的特征是存在反复出现的基因和细胞遗传学病变，这些病变用于风险分层和制定治疗决策。近年来，甲基化失调已得到广泛研究，并与成人AML的风险组和预后相关，然而，儿科AML的此类研究有限。此外，与成人AML中丰富的情况相比，儿科患者中诸如 、 或 等表观遗传基因的突变几乎不存在或很少见。在本研究中，我们评估了参加多中心AML02临床试验（NCT00136084）的儿科AML患者中与明确的细胞遗传学特征相关或无关的甲基化模式。我们的结果表明，与成人AML不同，胞嘧啶DNA甲基化在儿科AML中不会导致明显的独特聚类，然而，DNA甲基化特征与最常见和反复出现的细胞遗传学特征显著相关。对DNA甲基化和表达的配对评估确定了具有生物学相关性的基因和途径，这些基因和途径有望用于新的治疗策略。我们的结果进一步表明，表观遗传特征与既定的染色体/突变格局互补出现，这意味着癌基因或肿瘤抑制因子的失调可能同时利用遗传和表观遗传机制来影响对白血病发生至关重要的生物学途径。
