Enforced Expression of NUP98-HOXA10hd Fusion Gene in Multipotent Progenitors Support Long-term Hematopoiesis in primary mice [MP]

Allogenic hematopoietic stem cell (HSC) transplantation is widely used for treatment of blood disorders to re-establish long-term multi-lineage hematopoiesis. Enhance self-renewal potential of progenitor population to support hematopoiesis offer an alternative and complementary approach to achieve similar therapeutic effects. Nup98-Hoxa10hd fusion gene (NA) has been shown to confer expansion, anti-stress response and engraftment competitiveness on HSC. However, whether the ectopic expression of NA in multipotent progenitors (MPPs) could enhance their self-renewal potential and confer long-term multi-lineage hematopoiesis remains unknown. In this study, we showed that ectopic expression in MPPs confer long-term multi-lineage hematopoiesis in recipient mice. We further showed that NA upregulated pathways of cell cycle regulation, epigenetic regulation and response to stress in MPPs. These molecular traits increased the self-renewal potential of NA MPPs, which resulting in production of lineage-maintaining committed progenitor cells. Transcriptome analysis of NA myeloid progenitors identified genes regulating hematopoiesis, homeostasis, phosphorylation. In summary, we show that ectopic expression of Nup98-Hoxa10hd fusion gene enhance self-renwal potential of MPPs thus confer long-term multilineage repopulating capacity on MPPs, offering promising means to involve MPPs to augment cell source in clinical transplantation settings.

异体造血干细胞（allogenic hematopoietic stem cell, HSC）移植被广泛用于血液系统疾病的治疗，以重建长期多系造血功能。增强祖细胞群的自我更新潜能以支持造血，是实现同类治疗效果的替代与补充方案。已有研究显示，Nup98-Hoxa10hd融合基因（NA）可赋予造血干细胞扩增能力、抗应激能力与植入竞争力。然而，在多能祖细胞（multipotent progenitors, MPPs）中异位表达该融合基因，能否增强其自我更新潜能并赋予长期多系造血功能，目前仍不明确。本研究证实，在多能祖细胞中异位表达NA可使受体小鼠获得长期多系造血功能。进一步分析发现，NA可上调多能祖细胞中细胞周期调控、表观遗传调控以及应激反应相关通路。这些分子特征提升了NA修饰的多能祖细胞的自我更新潜能，进而产生维持谱系定向的定型祖细胞。对NA修饰的髓系祖细胞进行转录组分析，鉴定出一批调控造血、稳态及磷酸化过程的基因。综上，本研究证实异位表达Nup98-Hoxa10hd融合基因可增强多能祖细胞的自我更新潜能，使其获得长期多系重建造血能力，为临床移植场景中应用多能祖细胞扩充细胞来源提供了极具前景的策略。