Foxo1 Expressed in Osteoblasts Promotes the Leukemogenic Properties of β-Catenin By Activating Notch Signaling

Osteoblasts affect self-renewal and expansion of hematopoietic stem cells (HSCs) and homing of healthy hematopoietic and tumor cells into the bone marrow. Moreover, in the mouse, constitutive activation of b-catenin (Ctnnb1^CAosb mice) in osteoblasts is sufficient to alter the differentiation potential of myeloid and lymphoid progenitors and to trigger the development of acute myeloid leukemia (AML). Because the same genetic event is associated with AML development in humans we sought to better understand its molecular bases. For that purpose we examined in vivo whether FoxO1, a transcription factor known to interact with β-catenin, affects its AML inducing properties. Deleting one allele of FoxO1 mice from the osteoblasts of leukemic Ctnnb1^CAosb mice prevented the appearance of anemia, peripheral monocytosis, neutrophilia and lymphocytopenia that are otherwise observed in Ctnnb1^CAosb mice. Similarly, FoxO1 haploinsufficiency in osteoblasts of Ctnnb1^CAosb mice prevented the shift in the differentiation of HSCs to the myeloid lineage and the increase in the LSK+/CD150+/CD48- subset of long term repopulating HSC progenitors (LT-HSCs). Histological analysis showed that myeloid and megakaryocyte dysplasias observed in Ctnnb1^CAosb mice and associated with their AML phenotype were also rescued in Ctnnb1^CAosb;FoxO1_osb+/-animals. As a result FoxO1 haploinsufficiency in osteoblasts prevented the early lethality of Ctnnb1^CAosb mice since Ctnnb1^CAosb;FoxO1_osb+/-mice lived and were healthy for at least one year, the entire time that they were observed. At the molecular level FoxO1 interacts with b-catenin in osteoblasts to induce expression of the Notch ligand Jagged-1 which initiates the dysmyelopoiesis leading to AML. ChiP/Re-ChiP assays and transient transfection experiments showed that this interaction requires the formation of a b-catenin/Foxo1 complex at two distinct locations in the regions of the Jagged-1 promoter. It also leads to subsequent activation of Notch signaling in LT- HSC progenitors. These events induce the leukemogenic transformation of HSCs. These findings identify FoxO1 through its expression in osteoblasts as a factor affecting hematopoiesis and provide a molecular mechanism whereby the FoxO1/ activated b-catenin interaction results in AML. They further support the notion that targeting the bone marrow niche may be a new strategy to treat leukemia and raise the prospect that FoxO1 oncogenic properties may occur in other tissues.