Effect of Dis3 depletion on gene expression in hematopoietic stem cells of C57BL/6 mice. Effect of Dis3 depletion on gene expression in hematopoietic stem cells of C57BL/6 mice

Multiple myeloma (MM) is a plasma cell neoplasm that remains incurable regardless of the introduction of novel agents. Therefore, it is of necessity to decode the molecular mechanisms of myelomagenesis to identify novel therapeutic strategies. Recent advances in next-generation sequencing technologies have not only reconfirmed the significance of known driver events in MM but also have identified novel genetic alterations in MM. Importantly, mutations of DIS3 genes have been identified in ~10% of MM patients, and loss of heterozygosity at chromosome 13q that leads to deletion of one allele of DIS3 has been observed in ~ 40% of MM patients. However, the roles of DIS3 in hematopoiesis and myelomagenesis remain incompletely understood. Here we show that Dis3 prevents accumulation of DNA damage in hematopoietic cells, thereby supporting hematopoiesis. We also show that loss of Dis3 alone and in combination with c-MAF transgene in GC B cells do not exhibit plasma cell neoplasm in mice. Overall design: Hematopoietic stem cells of wild type and hematopoietic cell-specific Dis3-/- mice were isolated and subjected to RNA-seq (n = 2 mice).

多发性骨髓瘤（Multiple myeloma, MM）是一类浆细胞肿瘤，即便引入新型治疗药物仍无法治愈。因此，解析骨髓瘤发生的分子机制以发掘全新治疗策略实属必要。近年来，下一代测序技术（next-generation sequencing technologies）的进展不仅再次证实了已知MM驱动事件的重要性，还鉴定出了MM中新型的遗传改变。值得注意的是，约10%的MM患者中检测到DIS3基因的突变，且约40%的MM患者存在13号染色体长臂（chromosome 13q）的杂合性缺失（loss of heterozygosity），该缺失会导致DIS3基因的一个等位基因丢失。然而，DIS3在造血作用（hematopoiesis）及骨髓瘤发生过程中的作用仍未被完全阐明。本研究证实，Dis3可防止造血细胞（hematopoietic cells）内DNA损伤（DNA damage）的积累，从而维持造血功能。同时我们还发现，仅敲除Dis3，或是在生发中心B细胞（GC B cells）中共敲除Dis3与转入c-MAF转基因（c-MAF transgene），均无法在小鼠体内诱发浆细胞肿瘤。整体实验设计：分离野生型（wild type）及造血细胞特异性Dis3基因敲除小鼠的造血干细胞，进行RNA测序（RNA-seq），每组包含2只小鼠。