Intrinsic and extrinsic factors driving leukaemogenesis

The purpose of this thesis is to better understand how certain intrinsic and extrinsic factors contribute to the progression of leukaemia. For this reason, we focused on the study of two different genes (intrinsic factors) namely SLIT2 and MLL5 and on macrophages found in the bone marrow microenvironment (extrinsic factor). High expression of SLIT2 and MLL5 was associated with a better clinical outcome. In vitro and in vivo, we showed that low SLIT2 levels lead to increased leukaemic cell proliferation, while high levels of MLL5 improve the response to the differentiation agent all-trans retinoic acid. Additionally, we show that the emergence of leukaemia is associated with an increased frequency of immunosuppressive M2 macrophages. Patients with high M2 macrophages are linked to a worse clinical outcome. The interaction between leukaemic cells and M2 macrophages leads to increased engraftment in vivo and a more aggressive course of the disease. Furthermore, M2 macrophages lead to improved homing and resistance against phagocytosis, while also driving a more OXPHOS-like metabolism. The latter was also confirmed by single-cell analysis showing increased Fatty Acid Oxidation and NAD+ generation in AML-associated macrophages, which could be targeted therapeutically.