Physiologic Regulation of Hematopoiesis by Notch

描述（由申请人提供）：尽管炎症在癌症维持和进展中的作用日益得到认可，但特异性“炎症”骨髓（BM）生态位对正常和恶性造血的调节的贡献在很大程度上尚未被探索。最近出现了支持Notch信号在造血调节中的非细胞自主作用的证据；然而，Notch调控BM生态位完整性的细胞和分子机制仍然知之甚少。通过Notch/RBPJ功能缺失模型，我们发现RBPJ的缺失会导致BM微环境的炎症状态，导致髓系祖细胞的异常扩张。我们证明RBPJ作为microRNA miR-155的转录抑制因子，microRNA miR-155参与炎症和肿瘤发生。我们观察到，由于RBPJ转录抑制缺失导致的miR-155持续上调诱导NF-kB激活和BM生态位的全局炎症状态，特别是在内皮细胞中，导致髓细胞不受控制的扩张，最终导致骨髓增生性疾病的发展。值得注意的是，对骨髓增生性肿瘤（MPN）患者的分析显示，骨髓中miR155的表达升高。基于这些结果，我们假设Notch信号通过调节BM血管生态位中炎症张力的水平来促进造血稳态。因此，虽然脑基微环境中Notch信号的短暂抑制可能触发脑基损伤的生理性炎症回路，但Notch信号的持续抑制可能有助于骨髓增生性疾病的发生或进展。针对骨髓生态位对造血功能的调控，我们提出：1)明确内皮Notch信号在调节骨髓生态位完整性中的作用；2)确定miR155如何调节NF-Kb激活，绘制Notch/miR155/ NF-Kb通路及其对骨髓形成的影响，3)剖析人类MPN中Notch/miR155/ NF-Kb通路的分子基础。我们相信，这些研究将为在应激和恶性肿瘤条件下调节骨髓中造血细胞与其支持龛相互作用的分子机制提供重要见解，并将导致针对MPN炎症和疾病进展的策略。

DESCRIPTION (provided by applicant): Despite the increasingly recognized role of inflammation in cancer maintenance and progression, the contribution of specific "inflammatory" bone marrow (BM) niches to the regulation of normal and malignant hematopoiesis is largely unexplored. Evidence supporting a non-cell-autonomous role for Notch signaling in the regulation of hematopoiesis has recently emerged; however, the cellular and molecular mechanism(s) by which Notch regulates the integrity of the BM niche are still poorly understood. By using a Notch/RBPJ loss-of- function model, we showed that loss of RBPJ results in an inflammatory state of the BM microenvironment, leading to aberrant expansion of myeloid progenitors. We demonstrated that RBPJ functions as a transcriptional repressor of the microRNA miR-155, a microRNA involved in inflammation and tumorigenesis. We observed that persistent miR-155 up-regulation due to loss of RBPJ transcriptional repression induces NF-kB activation and a global state of inflammation in the BM niche, particularly in endothelial cells, leading to an uncontrolled expansion of myeloid cells and eventually to the development of a myeloproliferative disease. Of note, analysis of patients affected by myeloproliferative neoplasia (MPN) revealed elevated expression of miR155 in the BM. Based on these results, we hypothesize that Notch signaling contributes to hematopoietic homeostasis by regulating the level of the inflammatory tonus in the BM vascular niche. Thus, while transitory inhibition of Notch signaling in the BM microenvironment may trigger a physiologic inflammatory circuitry in response to BM injury, continuous inhibition of Notch signaling may contribute to the development or progression of myeloproliferative disorders. Focusing on the regulation of hematopoiesis by the BM niche and using several animal models, we propose: 1) to define the role of endothelial Notch signaling in regulating the integrity of the BM niche; 2) to determine how miR155 regulates NF-Kb activation and to map the Notch/miR155/NF-kB circuitry and its impact on myelopoiesis, and 3) to dissect the molecular underpins of the Notch/miR155/NF-kB pathway in human MPN. We believe that these studies will provide critical insights into the molecular mechanisms regulating the interactions of hematopoietic cells with their supportive niches in the BM during conditions of stress and malignancy, and that will lead to strategies to target inflammation and disease progression in MPN.