Regulation of hematopoiesis and leukemogenesis through the hematopoietic stem cell niche in chronic lymphocytic leukemia

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Chronic lymphocytic leukemia (CLL) is the most common leukemia in western countries. Despite advances in anti-leukemic therapy CLL remains incurable if not submitted to allogeneic bone marrow transplantation. Progressed disease is characterized by hematopoietic failure. The hematopoietic balance depends on the integrity of hematopoietic stem cells which is maintained through a tight regulation through the bone marrow niche. The architecture of the bone marrow niche is based on a complex arrangement of cellular and non-cellular constituents, where mesenchymal stem cells form a key player whose function is tightly regulated through the sympathetic nervous system. The aim of this research proposal is to explore to what extent hematopoietic failure can be referred to alterations to the hematopoietic stem cell niche and if lymphatic leukemic cells depend on the same microenvironmental cues like hematopoietic stem cells. In a model of acute myeloid leukemia we have recently shown how malignancies coopt the microenvironment to its own advantage. Leukemic infiltration was shown to induce a local sympathetic neuropathy, disrupting the quiescence of the niche and leading to an accumulation of osteoblast-primed mesenchymal stem cells which finally reinforces malignancy. In a TCL1 mouse model, with striking similarities to human CLL disease, preliminary data reveal alterations in the hematopoietic stem cell and niche regulating capacity of mesenchymal stem cells. At low leukemic burden mesenchymal stem cells already show a defect in the retention of hematopoietic stem and progenitor cells which results in an early mobilization. With increasing leukemic infiltration the hematopoietic stem cell regulating capacity of mesenchymal stem cells is impaired as well as their niche regulating properties are altered. In this research proposal we will dissect the architecture of the CLL bone marrow niche, assess its capacity to regulate healthy and malignant hematopoiesis and elucidate to what extent the observed niche alterations are reversible upon anti-leukemic treatment. These results will be finally validated in human CLL disease. These new insights will open therapeutic targets to restore healthy hematopoiesis and eradicate leukemic disease in its niche.