Genetic landscape of non-Down syndrome acute megkaryoblastic leukemia

To define the mutation spectrum in non-Down syndrome acute megkaryoblastic leukemia (non-DS-AMKL), we performed transcriptome sequencing on diagnostic blasts from 14 pediatric patients and validated our findings in a recurrency/validation cohort consisting of 34 pediatric and 28 adult AMKL leukemia samples. Our analysis identified a cryptic chromosome 16 inversion [inv(16)(p13.3q24.3)] in 27% of pediatric cases, which encodes a CBFA2T3-GLIS2 fusion protein. Expression of CBFA2T3-GLIS2 in Drosophila and murine hematopoietic cells induced bone morphogenic protein (BMP) signaling, and resulted in a marked increase in the self-renewal capacity of hematopoietic progenitors. These data suggest that expression of CBFA2T3-GLIS2 directly contributes to leukemogenesis.EGA study EGAS00001000379

为明确非唐氏综合征型急性巨核细胞白血病（non-Down syndrome acute megakaryoblastic leukemia, non-DS-AMKL）的突变谱，我们对14例儿科患者的诊断原始细胞（diagnostic blasts）开展了转录组测序（transcriptome sequencing），并在由34例儿科及28例成人急性巨核细胞白血病样本组成的复发/验证队列（recurrency/validation cohort）中验证了本研究结果。分析发现，27%的儿科病例存在隐匿性16号染色体倒位[inv(16)(p13.3q24.3)]，该倒位可编码CBFA2T3-GLIS2融合蛋白（CBFA2T3-GLIS2 fusion protein）。在果蝇（Drosophila）与小鼠造血细胞（murine hematopoietic cells）中表达CBFA2T3-GLIS2融合蛋白可激活骨形态发生蛋白（bone morphogenic protein, BMP）信号通路，并显著增强造血祖细胞（hematopoietic progenitors）的自我更新能力。上述研究数据表明，CBFA2T3-GLIS2融合蛋白的表达直接参与白血病发生（leukemogenesis）过程。本研究相关EGA研究编号为EGAS00001000379