title: Therapeutic targeting of NOTCH signaling ameliorates immune-mediated bone marrow failure of aplastic anemia.
abstract: Severe aplastic anemia (AA) is a bone marrow (BM) failure (BMF) disease frequently caused by aberrant immune destruction of blood progenitors. Although a Th1-mediated pathology is well described for AA, molecular mechanisms driving disease progression remain ill defined. The NOTCH signaling pathway mediates Th1 cell differentiation in the presence of polarizing cytokines, an action requiring enzymatic processing of NOTCH receptors by γ-secretase. Using a mouse model of AA, we demonstrate that expression of both intracellular NOTCH1(IC) and T-BET, a key transcription factor regulating Th1 cell differentiation, was increased in spleen and BM-infiltrating T cells during active disease. Conditionally deleting Notch1 or administering γ-secretase inhibitors (GSIs) in vivo attenuated disease and rescued mice from lethal BMF. In peripheral T cells from patients with untreated AA, NOTCH1(IC) was significantly elevated and bound to the TBX21 promoter, showing NOTCH1 directly regulates the gene encoding T-BET. Treating patient cells with GSIs in vitro lowered NOTCH1(IC) levels, decreased NOTCH1 detectable at the TBX21 promoter, and decreased T-BET expression, indicating that NOTCH1 signaling is responsive to GSIs during active disease. Collectively, these results identify NOTCH signaling as a primary driver of Th1-mediated pathogenesis in AA and may represent a novel target for therapeutic intervention.
authors.affiliation: Department of Veterinary and Animal Sciences, University of Massachusetts Amherst, MA 01003, USA.
authors.forename: Justine E
authors.initials: JE
authors.lastname: Roderick
authors.forename: Gabriela
authors.initials: G
authors.lastname: Gonzalez-Perez
authors.forename: Christina Arieta
authors.initials: CA
authors.lastname: Kuksin
authors.forename: Anushka
authors.initials: A
authors.lastname: Dongre
authors.forename: Emily R
authors.initials: ER
authors.lastname: Roberts
authors.forename: Janani
authors.initials: J
authors.lastname: Srinivasan
authors.forename: Chester
authors.initials: C
authors.lastname: Andrzejewski
authors.forename: Abdul H
authors.initials: AH
authors.lastname: Fauq
authors.forename: Todd E
authors.initials: TE
authors.lastname: Golde
authors.forename: Lucio
authors.initials: L
authors.lastname: Miele
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Minter
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors; D000741:Anemia, Aplastic / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D000818:Animals; D001853:Bone Marrow / Q000276:immunology* / Q000473:pathology*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D051881:Receptor, Notch1 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology
chemical_list: D004791:Enzyme Inhibitors; C497761:NOTCH1 protein, human; C497762:Notch1 protein, mouse; D051881:Receptor, Notch1; D053829:Amyloid Precursor Protein Secretases