Loss of β-catenin triggers oxidative stress and impairs hematopoietic regeneration

Abstract

Accidental or deliberate ionizing radiation exposure can be fatal due to widespread hematopoietic destruction. However, little is known about either the course of injury or the molecular pathways that regulate the subsequent regenerative response. Here we show that the Wnt signaling pathway is critically important for regeneration after radiation-induced injury. Using Wnt reporter mice, we show that radiation triggers activation of Wnt signaling in hematopoietic stem and progenitor cells. b-Catenin-deficient mice, which lack the ability to activate canonical Wnt signaling, exhibited impaired hematopoietic stem cell regeneration and bone marrow recovery after radiation. We found that, as part of the mechanism, hematopoietic stem cells lacking b-catenin fail to suppress the generation of reactive oxygen species and cannot resolve DNA double-strand breaks after radiation. Consistent with the impaired response to radiation, b-catenin-deficient mice are also unable to recover effectively after chemotherapy. Collectively, these data indicate that regenerative responses to distinct hematopoietic injuries share a genetic dependence on b-catenin and raise the possibility that modulation of Wnt signaling may be a path to improving bone marrow recovery after damage.

Hematopoietic and Leukemic Stem Cells Have Distinct Dependence on Tcf1 and Lef1 Transcription Factors

“…Our new observations on Tcf1/Lef1 deficiency reiterate the intrinsic requirements of Wnt-␤-catenin pathway in HSCs. Our data are also in line with a recent finding that ␤-catenin is required for HSC regeneration and BM recovery after radiation or chemotherapy (53).…”

Gaq signaling is required for the maintenance of MLL-AF9-induced acute myeloid leukemia

“…LSCs in AML rely primarily on OXPHOS to generate ATP for energy (10), and our results show that Gaq inhibition can impair the energy-generating capacity of MLL leukemic cells, increase ROS levels and lead to activation of a stress response associated with activation of Gadd45a. Our data revealing reduced β-catenin levels following Gaq inhibition are consistent with the effects of Gaq on mitochondrial activity being mediated via β-catenin activity, as recent studies have shown the crucial role for β-catenin in mitochondrial energy metabolism (11,12), and β-catenin is also critical in HSC for suppression of ROS levels (12). MLL AML has a particular dependence on β-catenin activity (1) and the findings presented here raise the possibility that targeting of -catenin and mitochondrial metabolism via Gaq may be a potential approach to reduction of leukemogenesis in MLL AML.…”

Frizzled-6 Regulates Hematopoietic Stem/Progenitor Cell Survival and Self-Renewal

“…Self-renewal is a crucial feature of HSCs, which allows them to replenish all hematopoietic lineages under conditions of BM stress (e.g., ablative chemotherapy, irradiation, infections, and injury) (34,39,40). Wnt signaling can play a critical role in HSPC selfrenewal, although the extent and source of signals are still under debate and likely involve different pathways under different circumstances (22,25,41). Canonical Wnt signaling is induced by myeloablative stress (25) and reportedly required for hematopoietic recovery in response to irradiation (41).…”