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越来越被认识到，但特异性“炎性”骨髓（BM）小生境对正常和恶性造血调节的贡献在很大程度上尚未探索。最近出现了支持Notch信号传导在造血调节中的非细胞自主作用的证据;然而，Notch调节BM小生境完整性的细胞和分子机制仍然知之甚少。通过使用Notch/RBPJ功能丧失模型，我们表明RBPJ的丧失导致BM微环境的炎症状态，导致骨髓祖细胞的异常扩增。我们证明了RBPJ作为microRNA miR-155的转录抑制因子发挥作用，miR-155是一种参与炎症和肿瘤发生的microRNA。我们观察到，由于RBPJ转录抑制的丧失而导致的持续性miR-155上调诱导了NF-κ B活化和BM小生境中的整体炎症状态，特别是在内皮细胞中，导致骨髓细胞的不受控制的扩增，并最终导致骨髓增殖性疾病的发展。值得注意的是，对受骨髓增生性肿瘤（MPN）影响的患者的分析显示BM中miR 155的表达升高。基于这些结果，我们假设Notch信号通过调节BM血管龛中的炎性紧张水平来促进造血稳态。因此，虽然在BM微环境中Notch信号传导的暂时抑制可触发响应于BM损伤的生理性炎症回路，但Notch信号传导的持续抑制可有助于骨髓增生性病症的发展或进展。围绕骨髓小生境对造血的调控，我们利用几种动物模型，提出：1）明确内皮Notch信号在调节骨髓小生境完整性中的作用; 2）确定miR 155如何调节NF-kb激活并绘制Notch/miR 155/NF-kB回路及其对骨髓生成的影响，以及3）剖析人MPN中Notch/miR 155/NF-kB途径的分子基础。我们相信，这些研究将提供重要的见解，调节造血细胞的相互作用的分子机制，在压力和恶性肿瘤的条件下，在BM中的支持壁龛，这将导致在MPN的炎症和疾病进展的目标战略。

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.