Molecular Basis for Myelodysplasia Induced by U2AF1 Mutations

U2AF1基因突变引起骨髓发育不良的分子基础 摘要 骨髓增生异常综合征(MDS)是以细胞减少和异常增生为特征的克隆性血液病 具有向急性髓系白血病转化风险增加的髓系细胞。当前的治疗方法 不足以治疗MDS。这表明有必要更好地了解MDS的分子机制。 并在MDS中确定新的治疗靶点。编码RNA剪接因子(U2AF1， SRSF2、SF3B1或ZRSR2)常见于MDS。U2AF1参与3‘端的识别 在前mRNA剪接过程中，U2 SnRNP的招募需要剪接位点。U2AF1突变已经被 在约11%的MDS病例中发现。然而，U2AF1突变在MDS和 U2AF1突变在MDS发病机制中的作用机制尚不清楚。要确定 突变的U2AF1在MDS中的作用，我们产生了一种新的条件性U2AF1-Q157R敲入小鼠。在……里面 初步研究，我们观察到U2AF1-Q157R突变体的造血表达导致了 骨髓中的巨细胞性贫血、红系发育不良和造血干细胞(HSC)的扩张。 我们还观察到EZH2的同时丢失和U2AF1-Q157R突变体的表达促进了 MDS的进展。我们假设U2AF1突变会触发RNA剪接改变，基因表达 HSPC的变化、DNA损伤和复制应激导致的异常造血和U2AF1 在MDS的进展过程中，突变与表观遗传调节因子突变协同作用。为了检验我们的假设，我们 提出三个具体目标。在目标1中，我们将研究U2AF1-Q157R突变和 骨髓发育不良的潜在分子机制。在目标2中，我们将确定生物和分子 U2AF1突变和共发生的表观遗传调控基因突变之间协同作用的基础 MDS的发病机制。在目标3中，我们将确定和测试U2AF1突变MDS的治疗策略。结果 这些研究将为MDS的分子发病机制提供新的见解，并可能导致新的 MDS的治疗途径。

Title: Molecular Basis for Myelodysplasia Induced by U2AF1 Mutations Abstract Myelodysplastic syndromes (MDS) are clonal hematologic disorders characterized by cytopenia and dysplasia of myeloid linage cells with an increased risk of transformation to acute myeloid leukemia. Current therapies are inadequate to treat MDS. This underscores a need to better understand the molecular mechanism of MDS and identify new therapeutic targets in MDS. Mutations in the genes encoding RNA splicing factors (U2AF1, SRSF2, SF3B1 or ZRSR2) are frequently observed in MDS. U2AF1 is involved in the recognition of the 3’ splice site required for recruitment of the U2 snRNP during pre-mRNA splicing. U2AF1 mutations have been identified in ~11% cases of MDS. However, the functional roles of U2AF1 mutations in MDS and the mechanism by which U2AF1 mutations contribute to MDS pathogenesis remain unclear. To determine the roles of mutant U2AF1 in MDS, we have generated a novel conditional U2AF1-Q157R knock-in mouse. In preliminary studies, we have observed that hematopoietic expression of U2AF1-Q157R mutant results in a macrocytic anemia, erythroid dysplasia and expansion of hematopoietic stem cells (HSC) in the bone marrow. We also have observed that concurrent loss of EZH2 and expression of U2AF1-Q157R mutant promotes rapid progression of MDS. We hypothesize that U2AF1 mutations trigger RNA splicing alterations, gene expression changes, DNA damage and replication stress in HSPC leading to aberrant hematopoiesis, and U2AF1 mutations cooperate with epigenetic regulator mutations in the progression of MDS. To test our hypothesis, we propose three Specific Aims. In Aim 1, we will investigate the consequences of U2AF1-Q157R mutation and underlying molecular mechanisms in myelodysplasia. In Aim 2, we will determine the biological and molecular basis for synergy between U2AF1 mutations and co-occurring epigenetic regulator mutations in the pathogenesis of MDS. In Aim 3, we will identify and test therapeutic strategies for U2AF1 mutant MDS. Results from these studies will provide new insights into the molecular pathogenesis of MDS and may lead to new therapeutic approach for treatment of MDS.