NOTCH signaling in immune-mediated bone marrow failure of aplastic anemia.

Severe aplastic anemia is a rare bone marrow failure disease with the majority of cases caused by aberrant immune destruction of blood progenitors. Although the Th1-mediated pathology of aplastic anemia is well-described, the molecular mechanisms that drive disease progression remain ill-defined. The NOTCH signaling pathway mediates Th1 differentiation in the presence of polarizing cytokines, an action requiring enzymatic processing of NOTCH receptors by γ- secretase. We used a mouse model of aplastic anemia to demonstrate that expression both of intracellular NOTCH1 (NOTCH1(IC)) and T-BET, a key transcription factor regulating Th1 differentiation, were increased in T cells in the spleen and bone marrow during active disease. Conditionally deleting NOTCH1 or administering γ-secretase inhibitors (GSI) in vivo, attenuated disease and rescued mice from lethal bone marrow failure. In peripheral T cells from patients with untreated aplastic anemia, NOTCH1(IC) was significantly elevated and was detected at the TBX21 promoter, showing NOTCH1 directly regulates the gene encoding T-BET. Treating patients' cells ex vivo with GSI lowered NOTCH1(IC) levels, decreased the level of NOTCH1 detectable at the TBX21 promoter, and also decreased T-BET expression, indicating NOTCH1 signaling is responsive to GSI during active disease. Collectively, these results identify NOTCH1 signaling as a primary driver of Th1-mediated pathogenesis in aplastic anemia and may represent a novel target for therapeutic intervention.