Replication timing alterations in leukemia reflect stable clinically-relevant changes in genome architecture [Repli-Chip]

Human B-lineage precursor acute lymphoid leukemias (BCP-ALLs) comprise a group of genetically and clinically distinct disease entities with features of differentiation arrest at known stages of normal B-lineage differentiation. We previously showed BCP-ALL cells display unique and clonally heritable DNA-replication timing (RT) programs; i.e., programs describing the variable order of replication and sub-nuclear 3D architecture of megabase-scale chromosomal units of DNA in different cell types. To determine the extent to which BCP-ALL RT programs mirror or deviate from specific stages of normal human B-cell differentiation, we transplanted immunodeficient mice with quiescent normal human CD34+ cord blood cells and obtained RT signatures of the regenerating B-lineage populations. We then compared these with RT signatures for leukemic cells from a large cohort of BCP-ALL patients of varied genetic subtype and outcome. The results identify BCP-ALL subtype-specific features that resemble specific stages of B-cell differentiation and features that appear associated with relapse. These results suggest the genesis of BCP-ALL involves alterations in RT that reflect biologically significant and clinically relevant leukemia-specific epigenetic changes that have potential as a novel genre of prognostic biomarkers. Genome-wide replication timing profiles were constructed from leukemia patients cells and normal differentiation stages of B-cell differentiation Please note that the processed data 'BALLanBlood_Alldata.txt' was generated from both array and HTS data (GSE130372 and GSE130373).人类B细胞系前体急性淋巴细胞白血病（BCP-ALLs）是一类在遗传学与临床特征上各具特点的疾病实体，其核心表现为细胞分化阻滞于正常B细胞系分化的已知特定阶段。我们此前的研究证实，BCP-ALL细胞拥有独特且可克隆遗传的DNA复制时序（DNA-replication timing, RT）程序——即描述不同细胞类型中百万碱基级染色体DNA单元的可变复制顺序与亚核三维结构的程序。为明确BCP-ALL的RT程序在多大程度上模拟或偏离正常人类B细胞分化的特定阶段，我们将静止态正常人类CD34+脐带血细胞移植至免疫缺陷小鼠体内，并获取了再生B细胞系群体的RT特征谱。随后我们将该特征谱与来自大量涵盖不同遗传亚型及临床结局的BCP-ALL患者的白血病细胞RT特征谱进行了比对。研究结果鉴定出BCP-ALL的亚型特异性特征：一类与B细胞分化特定阶段相似的特征，以及一类似乎与疾病复发相关的特征。上述结果提示，BCP-ALL的发生过程伴随RT程序的改变，这类改变反映了具有重要生物学与临床意义的白血病特异性表观遗传变化，有望成为一类新型预后生物标志物。本研究从白血病患者细胞及B细胞分化的正常阶段样本中构建了全基因组复制时序图谱。请注意，处理后的数据'BALLanBlood_Alldata.txt'由基因芯片与高通量测序（High-throughput sequencing, HTS）数据（GSE130372与GSE130373）整合生成。