Division of Genetics and Epidemiology, The Institute of Cancer Research, London, SM2 5NG, United Kingdom.
Department of Laboratory Medicine, Division of Clinical Genetics, Lund University, 221 85, Lund, Sweden.
Leukemia. 2019 Jan;33(1):1-14. doi: 10.1038/s41375-018-0184-z. Epub 2018 Jul 6.
Acute lymphoblastic leukaemia (ALL) is the most common paediatric malignancy. Genome-wide association studies have shown variation at 14q11.2 influences ALL risk. We sought to decipher causal variant(s) at 14q11.2 and the mechanism of tumorigenesis. We show rs2239630 G>A resides in the promoter of the CCAT enhancer-binding protein epsilon (CEBPE) gene. The rs2239630-A risk allele is associated with increased promotor activity and CEBPE expression. Depletion of CEBPE in ALL cells reduces cell growth, correspondingly CEBPE binds to the promoters of electron transport and energy generation genes. RNA-seq in CEBPE depleted cells demonstrates CEBPE regulates the expression of genes involved in B-cell development (IL7R), apoptosis (BCL2), and methotrexate resistance (RASS4L). CEBPE regulated genes significantly overlapped in CEBPE depleted cells, ALL blasts and IGH-CEBPE translocated ALL. This suggests CEBPE regulates a similar set of genes in each, consistent with a common biological mechanism of leukemogenesis for rs2239630 associated and CEBPE translocated ALL. Finally, we map IGH-CEBPE translocation breakpoints in two cases, implicating RAG recombinase activity in their formation.
急性淋巴细胞白血病（ALL）是最常见的儿科恶性肿瘤。全基因组关联研究表明，14q11.2 上的变异会影响 ALL 的风险。我们试图解析 14q11.2 上的因果变异和肿瘤发生机制。结果显示，rs2239630G>A 位于 CCAT 增强子结合蛋白 epsilon（CEBPE）基因的启动子内。rs2239630-A 风险等位基因与启动子活性和 CEBPE 表达增加相关。在 ALL 细胞中耗尽 CEBPE 会降低细胞生长，相应地 CEBPE 结合到电子传递和能量生成基因的启动子上。CEBPE 耗竭细胞的 RNA-seq 表明，CEBPE 调节与 B 细胞发育（IL7R）、凋亡（BCL2）和氨甲喋呤耐药（RASS4L）相关的基因表达。在 CEBPE 耗竭细胞、ALL blasts 和 IGH-CEBPE 易位 ALL 中，CEBPE 调节的基因显著重叠。这表明 CEBPE 在每种情况下都调节一组相似的基因，与 rs2239630 相关和 CEBPE 易位 ALL 的白血病发生具有共同的生物学机制一致。最后，我们在两个病例中定位了 IGH-CEBPE 易位断点，提示 RAG 重组酶活性参与了其形成。
