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.
While significant progresses have been achieved in the treatment of Chronic Myeloproliferative Leukemia (CML), treatment of the other Myeloproliferative Neoplasias (MPN) is still empiric and new ideas are needed to better understand the causes of these diseases and to prevent their evolution into Acute Myeloid Leukemia (which has a very poor prognosis). In this application, we propose to use in vivo models in combination with powerful genetic tools to test the hypothesis that a state of chronic inflammation in the bone marrow plays a critical role in maintaining and promoting progression of Myeloproliferative Neoplasia. Ultimately, accomplishment of this work will have a strong impact on the therapy for MPNs, providing a solid rationale for new therapeutic approaches that will include the use of specific inhibitors of inflammation during induction therapy and/or during remission to prevent relapse.
|Delgado-Calle, Jesus; Anderson, Judith; Cregor, Meloney D et al. (2016) Bidirectional Notch Signaling and Osteocyte-Derived Factors in the Bone Marrow Microenvironment Promote Tumor Cell Proliferation and Bone Destruction in Multiple Myeloma. Cancer Res 76:1089-100|
|Ghosh, Joydeep; Kobayashi, Michihiro; Ramdas, Baskar et al. (2016) S6K1 regulates hematopoietic stem cell self-renewal and leukemia maintenance. J Clin Invest 126:2621-5|
|Zhang, Huajia; Rodriguez, Sonia; Wang, Lin et al. (2016) Sepsis Induces Hematopoietic Stem Cell Exhaustion and Myelosuppression through Distinct Contributions of TRIF and MYD88. Stem Cell Reports 6:940-56|
|Tu, Xiaolin; Delgado-Calle, Jesus; Condon, Keith W et al. (2015) Osteocytes mediate the anabolic actions of canonical Wnt/Î²-catenin signaling in bone. Proc Natl Acad Sci U S A 112:E478-86|