Autophagy Sustains Hematopoiesis Through Targeting Notch

Autophagy is required for hematopoietic stem cell multilineage differentiation, but the underlying mechanism is unknown. Using a conditional mouse model and human leukemia cells, we uncovered a mechanistic link between autophagy and hematopoietic stem cell differentiation. Loss of autophagy in mouse hematopoietic stem cells diminished the bone marrow generation of functional blood cells, in particular lymphocytes, and resulted in a leukemic phenotype and elevated Notch signaling. Physiological autophagy activity in mice was inversely correlated with Notch signaling during adult hematopoietic stem cell differentiation, while pathologically low autophagy was associated with upregulated Notch signaling in dysfunctional hematopoietic stem cells of acute leukemia patients. Furthermore, we show that autophagy directly degraded intracellular Notch, the active form of Notch receptor cleaved from the full-length Notch molecule by γ-secretase. Finally, we show that hematopoietic multilineage differentiation potential was restored in autophagy defective hematopoietic stem and progenitor cells when their Notch signaling was abrogated either pharmacologically with γ-secretase inhibitor DAPT or genetically with RNA interference of Notch effector RBPJ. Hence, we propose that autophagy sustains hematopoiesis by direct targeting Notch.