Our understanding of the different layers of organization in tissues remains limited. Stem cell niches offer a tightly controlled environment and a unique opportunity to look into this question. Reductionist approaches have been proven highly efficient dissecting the complexity of stem cell niches in a unidirectional fashion. However, this approach fails to recognize the tri-dimensional complexity of tissue organization. Hence we propose a systems biology approach based on low input and single cell RNA sequencing of bone marrow niche populations in order to establish not only the molecular landscape of cells that comprise the stem cell niche in homeostasis and disease but also the lineage relationships that may exist between cells in the stroma. Using the mouse bone marrow niche during neoplastic transformation to acute myeloid leukemia (AML), we will first unravel the cellular and molecular interactions that constitute the tumor microenvironment during disease development and progression using multi parametric flow cytometry and RNA-sequencing. Information gathered from these experiments will also provide a list of molecular candidates for therapeutic intervention in AML. We will validate those candidate cell populations and genetic pathways by means of gain and loss-of-function assays in vitro and in vivo using murine models and primary human AML samples. Completion of our interdisciplinary project will provide, for the first time a complete transcriptional and cellular map of a tissue, revealing the heterotypic interactions that define the real nature of a tissue. Perhaps then we could start to appreciate the elegant complexity of the ecosystem that the stem cell and its niche share. I hope SyLeNCe will facilitate the description of novel vulnerabilities that could be explored therapeutically for the treatment of acute myeloid leukaemia having an impact on the quality of life and long-term survival of AML patients.
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