Germline RUNX1 Variation and Predisposition to Childhood Acute Lymphoblastic-RNA-Seq. Germline RUNX1 Variation and Predisposition to Childhood Acute Lymphoblastic-RNA-Seq

Somatic mutations of RUNX1, which encodes the myeloid and lymphoid transcriptional factor RUNX1, are common in both B- and T- acute lymphoid leukemia (ALL) and are associated with poor prognosis of T-ALL. However, there has been no comprehensive investigation of the pattern or prevalence of RUNX1 germline mutation in both B- and T-ALL. Here we report germline RUNX1 variants in 1.23% of B-ALL and 2.11% of T-ALL, identifying 31 unique variants in 62 B-ALL and 18 unique variants in 26 T-ALL children. The majority of frameshift and nonsense variants affected RUNX1 function in transcriptional regulation, hematopoiesis, and cellular proliferation. We identified JAK3 as the most frequent somatic mutation in T-ALL with RUNX1 variants. These results not only identify RUNX1 as a leukemia predisposition gene but also further underline the importance of germline genetic variants to the development of ALL Overall design: Investigation of gene expression pattern in parental or RUNX1 mutation (R232fs, Y287X and G365R) knock-in single clones (sc1, 22, 2, 5) of Jurkat T-ALL cells.

RUNX1编码髓系与淋巴系转录因子RUNX1，其体细胞突变（somatic mutation）在B细胞型和T细胞型急性淋巴细胞白血病（acute lymphoid leukemia, ALL）中均较为常见，且与T细胞急性淋巴细胞白血病的不良预后密切相关。然而，目前尚未有针对B细胞型与T细胞型急性淋巴细胞白血病中RUNX1生殖系突变（germline mutation）的模式与患病率开展的全面研究。本研究在1.23%的B细胞型急性淋巴细胞白血病病例以及2.11%的T细胞型急性淋巴细胞白血病病例中检出了RUNX1生殖系变异，在62例儿童B细胞型急性淋巴细胞白血病样本中鉴定出31种独特变异，在26例儿童T细胞型急性淋巴细胞白血病样本中鉴定出18种独特变异。绝大多数移码突变（frameshift mutation）与无义突变（nonsense mutation）均会影响RUNX1在转录调控、造血（hematopoiesis）以及细胞增殖过程中的功能。本研究还鉴定出JAK3是携带RUNX1变异的T细胞型急性淋巴细胞白血病病例中最常见的体细胞突变。上述研究结果不仅将RUNX1确定为白血病易感基因，同时进一步凸显了生殖系遗传变异在急性淋巴细胞白血病发生发展过程中的重要意义。整体实验设计：对Jurkat T细胞急性淋巴细胞白血病细胞的亲本株，以及敲入（knock-in）RUNX1突变（R232fs、Y287X与G365R）的单克隆细胞株（sc1、22、2、5）开展基因表达模式分析。