Physiologic expression of Srsf2(P95H) causes myeloid expansion, impaired competitive stem cell function and initiates the myeloproliferative/myelodysplastic syndrome in vivo [RNA-seq]

Mutations in the RNA splicing complex member SRSF2 are found frequently in myelodysplastic syndrome and related malignancies such as chronic myelomonocytic leukemia. These mutations cluster on proline 95, with P95H the most frequent. How SRSF2P95H mutations modify hematopoiesis and promote MDS/MPN development is not clear. We have established a conditionally activatable Srsf2P95H/+ knock-in allele which, when expressed within the hematopoietic stem cell populations caused profound myeloid bias, at the expense of erythroid and lymphoid cells, and a reduced frequency and competitive repopulation of HSCs. Long-term aging of Srsf2P95H/+ resulted in the development of MDS/MPN characterised by myeloid dysplasia and monocytosis. Reproducible key phenotypic features make this a mouse model suitable for mechanistic and preclinical MDS sudies.

RNA剪接复合物成员SRSF2的突变在骨髓增生异常综合征（myelodysplastic syndrome, MDS）及慢性粒单核细胞白血病（chronic myelomonocytic leukemia, CMML）等相关恶性肿瘤中频发出现。此类突变均聚集于脯氨酸95位点，其中P95H突变最为常见。目前，SRSF2P95H突变如何调控造血过程并促进MDS/骨髓增殖性肿瘤（myeloproliferative neoplasm, MPN）的发生发展，其机制尚未阐明。本研究已构建可条件性激活的Srsf2P95H/+敲入等位基因（knock-in allele）；当该等位基因在造血干细胞群中表达时，会引发显著的髓系分化偏倚，以红系与淋巴系细胞生成受损为代价，同时导致造血干细胞（hematopoietic stem cells, HSCs）的频率降低及竞争性重建造血能力减弱。对Srsf2P95H/+小鼠进行长期自然衰老饲养后，可观察到以髓系发育异常和单核细胞增多为特征的MDS/MPN表型。该模型可稳定重现关键疾病表型特征，因此适用于MDS的机制研究及临床前研究。