Role of AHR and HIF1α transcription factors in normal and chroniclymphocytic leukemia B lymphocytes

B-cells are present in most tumors and are contributing to inhibit the immune response and thus promote the development of the tumor mass by infiltrating the tumor and secreting immunoglobulins and immunosuppressive factors such as cytokines.In Chronic Lymphocytic Leukemia (CLL), both normal B lymphocytes (LB)and leukemic B lymphocytes (LB-CLL) may exhibit immunosuppressive characteristics, mainly by the secretion of IL-10, which inhibits certain functions of T lymphocytes and stimulates the proliferation of LB, their survival and antibody production.The transcription factors (TF) AHR (Aryl hydrocarbon receptor) and HIF1α(Hypoxia-Inducible Factor-1 alpha) regulate the cellular adaptation to the stresses of the environment. AHR is activated by hydrocarbon derivatives ortoxins but also by tryptophan derivatives secreted by the tumor cells. We have also shown that IFN-g stimulated LB-CLL cells capture tryptophan and
metabolize it with the enzyme Ido-1. HIF-1a is stabilized in response to hypoxia. Recent studies have shown that these two TFs regulate certain key functions of B cells. This project aims to study these TFs in B cells ofCLL patients and to determine the consequences of their inhibition in vivo in normal B cells under physiological conditions, as well as in the Blymphocytes of CLL.To this end, Ahr and Hif1α were invalidated in B lymphocytes by crossingCd19Cre/Cre mice with mice floxed for the genes Ahr or Hif1a The seconditional KO mice will be used to study their roles in normal LB functions but also in LBs from LLC. Adoptive transfers of malignant splenocytes fromEμ-TCL1 mice will also make possible to study the role of normal LB (ctlr vscKO) in the development of leukemia.