Pathogenesis of ELANE-Mutant Severe Neutropenia Revealed by Induced Pluripotent Stem Cells Open Access Deposited

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Date Uploaded: 02/08/2017
Date Modified: 04/10/2017

Severe congenital neutropenia (SCN) is often associated with inherited heterozygous point mutations in ELANE, which
encodes neutrophil elastase (NE). However, a lack of appropriate models to recapitulate SCN has substantially hampered
the understanding of the genetic etiology and pathobiology of this disease. To this end, we generated both normal and SCN
patient–derived induced pluripotent stem cells (iPSCs), and performed genome editing and differentiation protocols that
recapitulate the major features of granulopoiesis. Pathogenesis of ELANE point mutations was the result of promyelocyte
death and differentiation arrest, and was associated with NE mislocalization and activation of the unfolded protein
response/ER stress (UPR/ER stress). Similarly, high-dose G-CSF (or downstream signaling through AKT/BCL2) rescues
the dysgranulopoietic defect in SCN patient–derived iPSCs through C/EBPβ-dependent emergency granulopoiesis. In
contrast, sivelestat, an NE-specific small-molecule inhibitor, corrected dysgranulopoiesis by restoring normal intracellular
NE localization in primary granules; ameliorating UPR/ER stress; increasing expression of CEBPA, but not CEBPB; and
promoting promyelocyte survival and differentiation. Together, these data suggest that SCN disease pathogenesis includes
NE mislocalization, which in turn triggers dysfunctional survival signaling and UPR/ER stress. This paradigm has the
potential to be clinically exploited to achieve therapeutic responses using lower doses of G-CSF combined with targeting to
correct NE mislocalization.

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Journal Title
  • Pathogenesis of ELANE-mutant severe neutropenia revealed by induced pluripotent stem cells
  • This work was part of a pilot "mediated-deposit model" where library staff found potential works, later submitted for faculty review



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