The Role of Stromal CYP26 in Myelodysplastic Syndromes

骨髓增生异常综合征(MDS)是一种异质性造血干细胞(HSC)疾病 以骨髓发育不良和外周血细胞减少为特征。治疗性的 改善细胞减少症，从而解决发病率和死亡率的主要来源的办法 在MDS中，依赖促红细胞生成素刺激剂(ESA)和DNA去甲基化药物(DMA)。 这些策略诱导分化并改善一小部分患者的细胞减少症，但他们的 回应是短暂的。维甲酸在分化正常和非小细胞肺癌中的重要作用 恶性造血细胞。维甲酸类化合物可以与ESA和表观遗传剂在 MDS患者的子集，但他们作为单一药物或在 上述组合。骨髓间充质干细胞(MSCs)表达 细胞色素P26，一种维甲酸失活酶，控制干细胞中的维甲酸稳态 利基维持稳定状态的造血。恶性细胞可能劫持对间质的控制 CYP26的活动，以创造允许的微环境。为此，我们展示了恶性的 浆细胞分泌Sonic Hedgehog(SHH)诱导间质细胞色素P26表达 在多发性骨髓瘤(MM)中创造维甲酸低利基和耐药性。刺猬(HH) 信号转导也参与了MDS的发病机制。例如，间充质干细胞 MDS患者骨髓基质中存在HH途径异常。通过以下方式治疗 DMA恢复间质HH活性的平衡，从而导致MDS存活率下降 细胞。此外，我们的初步数据显示，MDS细胞分泌HH配体，因此， 在他们的骨髓微环境中改变CYP26表达的可能性。最重要的是 这一假设是，异常的基质细胞色素P26导致视黄素低生态位在 骨髓导致MDS中的分化障碍和细胞减少，以及缺乏 维甲酸类药物在这种疾病中的临床益处。K08奖提供了 这项申请的资格是为了研究基质细胞色素P26在维持心脏功能中的作用 体内HSC正常。在这里，我们建议阐明控制基质细胞色素P26的机制 Sonic Hedgehog下游基因的表达及其对MDS病理生理和免疫功能的影响 对治疗的反应。

Myelodysplastic syndromes (MDS) are heterogeneous hematopoietic stem cell (HSC) disorders characterized by bone marrow (BM) dysplasia and peripheral cytopenias. Therapeutic approaches to improve cytopenias and thus address the major source of morbidity and mortality in MDS rely on erythropoietin stimulating agents (ESA) and DNA-demethylating agents (DMA). These strategies induce differentiation and improve cytopenias in a fraction of patients but their responses are short lived. Retinoids play important roles in differentiation of normal and malignant hematopoietic cells. Retinoids can cooperate with ESA and epigenetic agents in a subset of MDS patients but they have limited clinical benefit either as single agents or in aforementioned combinations. Bone marrow mesenchymal stroma cells (MSCs) expresses CYP26, a retinoic acid inactivating enzyme and controls retinoid homeostasis in the stem cell niche to maintain steady state hematopoiesis. Malignant cells may hijack control of stromal CYP26 activity to create permissive microenvironments. To this end, we showed that malignant plasma cells secrete Sonic Hedgehog (SHH) to induce stromal CYP26 expression and thus create retinoid low niches and drug resistance in multiple myeloma (MM). Hedgehog (HH) signaling has also been implicated in the pathogenesis of MDS. For instance, mesenchymal stroma isolated from BM of patients with MDS has dysregulated HH pathway. Treatment with DMA restores balance in stromal HH activity and thus contributes to reduced survival of MDS cells. In addition, our preliminary data show that MDS cells secrete HH ligands and thus, have the potential to alter CYP26 expression in their BM microenvironment. The overarching hypothesis of this proposal is that abnormal stromal CYP26 leading to retinoid low niches in the BM contributes to impaired differentiation and cytopenias seen in MDS as well as to the lack of clinical benefit of pharmacological retinoids in this disease. The K08 award that provides the eligibility for this application is design to study the role of stromal CYP26 in maintenance of normal HSC in vivo. Here, we propose to elucidate the mechanisms that control stromal CYP26 expression downstream of Sonic Hedgehog and their impact on MDS pathophysiology and response to treatment.