The leukemic stem cell niche - parallels to its physiological counterpart

点击翻译按钮获取中文摘要

Hematopoietic stem cells reside in specific niches that regulate their survival, proliferation, selfrenewal or differentiation in the bone marrow. Parallels between normal stem cells and leukemia stem cells and their regulation within specific niches have been suggested.It has been shown that the sympathetic nervous system regulates hematopoietic stem cells and their progenitors in the bone marrow. Depending on the adrenergic signaling within the bone marrow circulating HSCs and their progenitors exhibit robust circadian oscillations. Moreover, a novel key figure in the hematopoietic stem cell niche has been identified as nestin-positive cells, which proved to behave like mesenchymal stem cells. Emerging data have highlighted the role of the autonomous nervous system in regulation of cancer initiation and dissemination using the example of prostate cancer.The purpose of this study is to elaborate the role of the autonomous nervous system, the circadian rhythm and nestin-positive mesenchymal stem cells in the pathogenesis of acute myeloid leukemia. We hypothesize that the sympathetic nervous system regulates leukemia initiation and expansion, disruption of the circadian rhythm influences growth of the leukemic clone and after depletion of nestin-positive cells leukemia development is going to be impaired.In this study we are working with transgenic and xenogeneic mouse models, performing genetic, pharmacological and surgical denervation and using state-of-the-art imaging.The aim is to compare the physiological and malignant niche and use differences for targeted antineoplastic therapies to selectively deplete the repopulating fraction of leukemia cells and eventually overcome their drug resistance.