Reduced EIF6 dosage attenuates TP53 activation in models of Shwachman-Diamond syndrome
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187778.2-20250404071443-covered-4fa089109ce452e764bbb8648b44a723.pdf
Description
Published version
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2.49 MB
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f5bf56658a4d4d60e70b79a146fe6444
Author(s)
Oyarbide, Usua
Bezzerri, Valentino
Staton, Morgan
Boni, Christian
Shah, Arish
Cipolli, Marco
Calo, Eliezer
Corey, Seth J
Date Issued
February 18, 2025
Journal
Journal of Clinical Investigation
Publisher
American Society for Clinical Investigation
Version
Final published version
Abstract
Shwachman-Diamond syndrome (SDS) is characterized by neutropenia, exocrine pancreatic insufficiency, and bony abnormalities with an increased risk of myeloid neoplasia. Almost all cases of SDS result from biallelic mutations in Shwachman-Bodian-Diamond syndrome (SBDS). SBDS interacts with elongation factor–like 1 (EFL1) to displace eukaryotic initiation factor 6 (EIF6) from the 60S ribosomal subunit. Released EIF6 permits the assembly of ribosomal large and small subunits in the cytoplasm. Decreased EIF6 levels due to haploinsufficiency or missense mutations, which lead to decreased protein expression, may provide a somatic genetic rescue and antileukemic effects. We observed accumulation of EIF6 protein in sbds-KO zebrafish models, confirmed this accumulation in patient-derived tissues, and correlated these with changes in ribosomal proteins and tumor protein p53 (TP53) pathways. The mechanism of action for this adaptive response is unknown. To address this, we generated eif6-KO zebrafish, which do not survive more than 10 days after fertilization. We also created 2 mutants with low Eif6 expression, i.e., 5%–25% of WT levels, that could survive until adulthood. We bred them with sbds-null strains and analyzed their phenotype and biochemical properties. Low Eif6 levels reduced Tp53 pathway activation but did not rescue neutropenia in Sbds-deficient zebrafish. Further studies elucidating the interplay between SBDS, EIF6, and TP53 and cellular stress responses offer promising insights into SDS pathogenesis, somatic genetic rescue, and therapeutic strategies.
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DOI of Published Version
https://doi.org/10.1172/jci187778
