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Disease-on-the-dish Modeling of ELANE Start Codon Mutations in Human Severe Congenital Neutropenia

Lee, Yarim
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1627668048604927

Abstract Details

2021, MS, University of Cincinnati, Medicine: Biomedical Research Technology.
Severe congenital neutropenia (SCN) is a heterozygous dominant autosomal hematopoietic disorder associated with differentiation arrest and cell death at the promyelocytic/myelocytic stages of granulopoietic differentiation, resulting in very low levels or absence of mature neutrophils in bone marrow and peripheral blood. Granulocyte-colony stimulating factor (G-CSF) is the cornerstone of therapy for this disease, however some mutations are associated with G-CSF resistance. Mutation in the ATG start codon of the ELANE gene interestingly gives rise to alternatively translated truncated peptides of neutrophil elastase (NE). The alternatively translated peptides are frequently misfolded which generates insoluble protein aggregates which induces apoptosis and cell death of granulocyte precursors. The cell death of ATG mutant promyelocytes is not due to unfolded protein response pathway mediated endoplasmic reticulum stress (UPR/ER-stress). The insoluble protein aggregates induce aggrephagy processes, as evidenced by the NE co-localization, with adaptor protein p62 in promyelocytes derived from ATG mutant patient’s iPSC and GTG knock-in iPSC lines. The ELANE ATG mutant granulopoiesis is insensitive to high concentration G-CSF therapy. We found that SERF1, a protein known to induce insoluble protein amyloid formation in neurons, is upregulated in ATG mutant promyelocytes. Downregulation of SERF1 rescues the survival of ATG mutant promyelocytes and myelocytes. Taken together, our data illustrates the mechanism of SCN associated with ATG mutations of ELANE and demonstrates the consequence of aggrephagy, which opens a new avenue for the therapy of G-CSF resistant SCN patients.
Rashmi Hegde, Ph.D. (Committee Chair)
Jose Cancelas-Perez, M.D. Ph.D. (Committee Member)
Carolyn Lutzko, Ph.D. (Committee Member)
28 p.
Biology
Severe Congenital Neutropenia; neutropenia; Hematopoiesis; aggregphagy; protein aggregation

Recommended Citations

Citations

  • Lee, Y. (2021). Disease-on-the-dish Modeling of ELANE Start Codon Mutations in Human Severe Congenital Neutropenia [Master's thesis, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1627668048604927

    APA Style (7th edition)

  • Lee, Yarim. Disease-on-the-dish Modeling of ELANE Start Codon Mutations in Human Severe Congenital Neutropenia. 2021. University of Cincinnati, Master's thesis. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1627668048604927.

    MLA Style (8th edition)

  • Lee, Yarim. "Disease-on-the-dish Modeling of ELANE Start Codon Mutations in Human Severe Congenital Neutropenia." Master's thesis, University of Cincinnati, 2021. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1627668048604927

    Chicago Manual of Style (17th edition)

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