Department of Cellular and Molecular Immunology, Max Planck Institute of Immunobiology and Epigenetics, 79108 Freiburg, Germany.
Laboratory of Single-Cell Biology, Max Planck Institute of Immunobiology and Epigenetics, 79108 Freiburg, Germany.
Genes Dev. 2020 Nov 1;34(21-22):1503-1519. doi: 10.1101/gad.340216.120. Epub 2020 Oct 1.
and mutations are associated with the development of B progenitor acute lymphoblastic leukemia (B-ALL) in humans. To understand the molecular networks driving leukemia in the (dHet) mouse model for B-ALL, we interrogated the transcriptional profiles and chromatin status of leukemic cells, preleukemic dHet pro-B, and wild-type pro-B cells with the corresponding EBF1 and Pax5 cistromes. In dHet B-ALL cells, many EBF1 and Pax5 target genes encoding pre-BCR signaling components and transcription factors were down-regulated, whereas Myc and genes downstream from IL-7 signaling or associated with the folate pathway were up-regulated. We show that blockade of IL-7 signaling in vivo and methotrexate treatment of leukemic cells in vitro attenuate the expansion of leukemic cells. Single-cell RNA-sequencing revealed heterogeneity of leukemic cells and identified a subset of wild-type pro-B cells with reduced and enhanced expression that show hallmarks of dHet B-ALL cells. Thus, EBF1 and Pax5 may safeguard early stage B cells from transformation to B-ALL by limiting IL-7 signaling, folate metabolism and expression.
和突变与人类 B 祖细胞急性淋巴细胞白血病 (B-ALL) 的发展有关。为了了解 B-ALL 的 (dHet) 小鼠模型中驱动白血病的分子网络，我们利用相应的 EBF1 和 Pax5 顺式作用元件研究了白血病细胞、前白血病 dHet pro-B 和野生型 pro-B 细胞的转录谱和染色质状态。在 dHet B-ALL 细胞中，许多编码 pre-BCR 信号成分和转录因子的 EBF1 和 Pax5 靶基因下调，而 Myc 和与 IL-7 信号或叶酸途径相关的基因上调。我们表明，体内阻断 IL-7 信号和体外白血病细胞的甲氨蝶呤治疗可减弱白血病细胞的扩增。单细胞 RNA-seq 揭示了白血病细胞的异质性，并鉴定出一小部分野生型 pro-B 细胞，其 表达降低，而 表达增强，表现出 dHet B-ALL 细胞的特征。因此，EBF1 和 Pax5 可能通过限制 IL-7 信号、叶酸代谢和 表达来保护早期 B 细胞免于转化为 B-ALL。
