Lymphocyte Development and Disease Group, Josep Carreras Leukaemia Research Institute (IJC), Ctra. de Can Ruti, Camí de les Escoles s/n, 08916 Barcelona, Spain.
Int J Mol Sci. 2021 Mar 18;22(6):3127. doi: 10.3390/ijms22063127.
B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is a highly aggressive malignancy, with poorer prognosis in infants than in adults. A genetic signature has been associated with this outcome but, remarkably, leukemogenesis is commonly triggered by genetic alterations of embryonic origin that involve the deregulation of chromatin remodelers. This review considers in depth how the alteration of epigenetic profiles (at DNA and histone levels) induces an aberrant phenotype in B lymphocyte progenitors by modulating the oncogenic drivers and tumor suppressors involved in key cancer hallmarks. DNA methylation patterns have been widely studied in BCP-ALL and their correlation with survival has been established. However, the effect of methylation on histone residues can be very different. For instance, methyltransferase gene participates in chromosomal rearrangements with several partners, imposing an altered pattern of methylated H3K4 and H3K79 residues, enhancing oncogene promoter activation, and conferring a worse outcome on affected infants. In parallel, acetylation processes provide an additional layer of epigenetic regulation and can alter the chromatin conformation, enabling the binding of regulatory factors. Therefore, an integrated knowledge of all epigenetic disorders is essential to understand the molecular basis of BCP-ALL and to identify novel entry points that can be exploited to improve therapeutic options and disease prognosis.
B 细胞前体急性淋巴细胞白血病（BCP-ALL）是一种高度侵袭性恶性肿瘤，婴儿的预后比成人差。已经有一个遗传特征与该结果相关，但值得注意的是，白血病的发生通常是由涉及染色质重塑因子失调的胚胎起源的遗传改变引发的。这篇综述深入探讨了表观遗传谱（在 DNA 和组蛋白水平上）的改变如何通过调节涉及关键癌症特征的致癌驱动因子和肿瘤抑制因子，在 B 淋巴细胞祖细胞中诱导异常表型。BCP-ALL 中广泛研究了 DNA 甲基化模式，并已确定其与存活率的相关性。然而，组蛋白残基上的甲基化作用可能非常不同。例如，甲基转移酶基因参与与多个伙伴的染色体重排，导致 H3K4 和 H3K79 残基的甲基化模式改变，增强致癌基因启动子的激活，并对受影响的婴儿产生更差的结果。同时，乙酰化过程提供了一个额外的表观遗传调控层，可以改变染色质构象，使调节因子能够结合。因此，综合了解所有的表观遗传紊乱对于理解 BCP-ALL 的分子基础以及确定可以用来改善治疗选择和疾病预后的新切入点至关重要。
