Modeling myelodysplasia

项目总结 骨髓增生异常综合征(MDS)是一种随着年龄的增长而增加的造血干细胞(HSC)癌症 人口和癌症幸存者。治疗MDS的唯一有效方法是异基因干细胞移植 在大多数MDS患者中有明显的局限性。因此，护理标准侧重于 低甲基化药物(HMA)、氮胞苷(AZA)和地西他滨(DAC)，这些都会导致耐药性 和疾病的进展。迫切需要新的疗法；然而，目前还没有强有力的模型来治疗 MDS加速临床前测试。我们已经产生了一个突破性的人性化异种移植接受者 小鼠模型，消除了条件反射，促进了原发MDS的植入。我们将验证 治疗前诊断MDS患者材料的单细胞遗传学和基因组特征模型 并将相同的细胞移植到人源化的小鼠身上，清楚地揭示了 异种移植。接下来，我们将在小鼠模型中建立AZA的药效学终点，并应用 AZA对模型的经验性推导剂量。人类MDS材料将被捕获用于单个细胞 从患者和异种移植两方面分析AZA后的治疗。多元组学的比较分析将 深入确定MISTRG-W41用于MDS临床前测试的效用，通过说明以下程度 在异种移植中，患者中受Aza影响的程序也发生了类似的变化。这种深层次的分子、基因类型和 将建立对HMA对MDS亚克隆和分级细胞成分影响的表型理解 新靶向治疗药物作为替代物、同期或HMA后的比较基础 治疗方法。

PROJECT SUMMARY Myelodysplastic Syndromes (MDS) are a cancer of the hematopoietic stem cell (HSC) on the rise in the aging population and cancer survivors. The only curative treatment for MDS is allogeneic stem cell transplantation with marked limitations in the majority of MDS patients. As a result, standard-of-care focuses on hypomethylating agents (HMA) azacytidine (AZA) and decitabine (DAC), which invariably result in resistance and disease progression. There is a dire need for new therapeutics; however, there are no robust models of MDS to accelerate preclinical testing. We have generated a breakthrough humanized xenograft-recipient mouse model which eliminates conditioning and facilitates engraftment of primary MDS. We will validate the model by single-cell genetic and genomic characterization of diagnostic MDS patient material before therapy and of the same cells engrafted in humanized mice, clearly dellineating the transcriptional impact of xenografting. Next, we will establish pharmacodynamic endpoints for AZA within the mouse model and apply the empirically-derived dose of AZA to the model. Human MDS material will be captured for single cell analyses post-AZA therapy from both patients and xenografts. The multi-omics comparative analyses will incisively determine the utility of MISTRG-W41 for MDS preclinical testing, by illustrating the extent to which AZA-affected programs in patients are similarly changed in the xenograft. This deep molecular, genotypic, and phenotypic understanding of HMA effects on subclonal and hierarchical cellular compositions of MDS will build the basis for comparison of novel-targeted-therapeutic agents as alternatives, concurrent, or post-HMA therapeutic approaches.