PRMT1和RBM15是造血干细胞巨核系分化中的重要蛋白，它们相互作用影响人类造血干细胞巨核系分化的研究未见报到，它们之间的信号传导机制也不明。已发现RBM15功能缺陷存在于急性巨核细胞白血病（AMKL）患者中，PRMT1在AMKL中的意义不明。本研究利用多种分子生物学方法、基因芯片技术，以CD34+脐血细胞和MEG-01细胞为研究对象，揭示PRMT1和RBM15蛋白共同影响人类造血干细胞巨核系分化的信号传导机制；同时收集AMKL患者骨髓标本，研究PRMT1的表达和意义，应用PRMT1抑制剂筛选系统，获得有效调节巨核细胞分化的抑制剂，评价其作为AMKL患者靶向治疗新药的可行性。该研究不仅丰富了人类造血干细胞巨核系分化的基础理论，也获知了PRMT1蛋白作为AMKL潜在治疗靶点和PRMT1抑制剂作为靶向治疗新药的价值。

RBM15 is the fusion partner for RBM15-MAL translocation found in childhood acute megakaryoblastic leukemia (AMKL). RBM15 is required for the maintenance of the homeostasis of long term hematopoietic stem cells and for differentiation of B cells and megakaryocyte. RBM15 encodes an RNA binding protein important for Notch mediated transcriptional regulation and RNA export pathways. Still the detailed molecular mechanisms on how RBM15 controls hematopoiesis are not known. We have identified that the RBM15 protein stability is controlled by PRMT1. Furthermore, isoform V2 is the most efficient isoform to degrade RBM15. We are very excited to investigate whether methylation is a novel signal for triggering ubiquitylation. If that is the case, we will purify the E3 ligase and the ligase complex responsible for RBM15 ubiquitylation. Based on our preliminary data that PRMT1 V2 level is dynamically regulated during the megakaryocyte differentiation, we hypothesize PRMT1V2 regulates megakaryocyte differentiation via regulating the stability of RBM15. In this project, we are going to dissect the mechanisms on how the RBM15 is degraded by PRMT1 and on how RBM15 and PRMT1 function together to program the megakaryocyte differentiation. We will investigate the role of PRMT1 in AMKL patients and RBM15-MAL initiated AMKL using primarily human cord blood cell transduced with RBM15-MAL gene. A cell based PRMT1 assay is being developed based on PRMT1 dependent RBM15 stability change. A few PRMT1 inhibitors available to us now will be used to optimize the cell-based PRMT1 assay. The objective is to explore the feasibility of target PRMT1 for leukemia treatment.