Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • Vascular Malformations (Apr 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact

Submit a comment

Reduced EIF6 dosage attenuates TP53 activation in models of Shwachman-Diamond syndrome
Usua Oyarbide, … , Eliezer Calo, Seth J. Corey
Usua Oyarbide, … , Eliezer Calo, Seth J. Corey
Published February 18, 2025
Citation Information: J Clin Invest. 2025;135(8):e187778. https://doi.org/10.1172/JCI187778.
View: Text | PDF
Research Article Genetics Hematology Oncology Article has an altmetric score of 1

Reduced EIF6 dosage attenuates TP53 activation in models of Shwachman-Diamond syndrome

  • Text
  • PDF
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.

Authors

Usua Oyarbide, Valentino Bezzerri, Morgan Staton, Christian Boni, Arish Shah, Marco Cipolli, Eliezer Calo, Seth J. Corey

×

Guidelines

The Editorial Board will only consider comments that are deemed relevant and of interest to readers. The Journal will not post data that have not been subjected to peer review; or a comment that is essentially a reiteration of another comment.

  • Comments appear on the Journal’s website and are linked from the original article’s web page.
  • Authors are notified by email if their comments are posted.
  • The Journal reserves the right to edit comments for length and clarity.
  • No appeals will be considered.
  • Comments are not indexed in PubMed.

Specific requirements

  • Maximum length, 400 words
  • Entered as plain text or HTML
  • Author’s name and email address, to be posted with the comment
  • Declaration of all potential conflicts of interest (even if these are not ultimately posted); see the Journal’s conflict-of-interest policy
  • Comments may not include figures
This field is required
This field is required
This field is required
This field is required
This field is required
This field is required
Rich Text Editor, eletter_body
Editor toolbarsClipboard/Undo CutKeyboard shortcut Ctrl+X CopyKeyboard shortcut Ctrl+C PasteKeyboard shortcut Ctrl+V Paste as plain textKeyboard shortcut Ctrl+Alt+Shift+V Paste from Word UndoKeyboard shortcut Ctrl+Z RedoKeyboard shortcut Ctrl+YEditing Find Replace Select All Spell Check As You TypeLinks LinkKeyboard shortcut Ctrl+K Unlink AnchorForms Form Checkbox Radio Button Text Field Textarea Selection Field Button Image Button Hidden FieldTools Maximize Show BlocksDocument Source Save New Page Preview Print TemplatesBasic Styles BoldKeyboard shortcut Ctrl+B ItalicKeyboard shortcut Ctrl+I UnderlineKeyboard shortcut Ctrl+U Strikethrough Subscript Superscript Copy FormattingKeyboard shortcut Ctrl+Shift+C Remove FormatParagraph Insert/Remove Numbered List Insert/Remove Bulleted List Decrease Indent Increase Indent Block Quote Create Div Container Align Left Center Align Right Justify Text direction from left to right Text direction from right to left Set languageStylesStylesStylesFormatFormatFontFontSizeSizeColors Text Color Background Color
Press ALT 0 for help
◢Elements path 

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts

Posted by 2 X users
See more details