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<p>Diamond Blackfan anemia syndrome (DBAS) is a congenital ribosomopathy caused by haploinsufficiency of ribosomal proteins (RPs), but how RP stoichiometry and activity regulates erythroid development remains enigmatic. Using in vivo models, we uncover divergent functions for the small and large ribosomal subunit proteins RPS19 and RPL5 in fetal hematopoiesis. While RPL5 haploinsufficiency causes hematopoietic stem and progenitor cell (HSPC) accumulation and prenatal lethality via p53-mediated ferroptosis of mature erythroid progenitors, RPS19 haploinsufficiency leads to HSPC depletion and impaired erythroid expansion through p53-dependent apoptosis. The latter is accompanied by translational and transcriptional dysregulation, including the upregulation of <i>RUNX1</i>, which is also observed in RPS- haploinsufficient DBAS patients. Importantly, <i>Runx1</i> deletion in RPS19-haploinsufficient mice partially rescues HSPC numbers. These findings reveal subunit-specific RP functions in controlling fetal hematopoiesis and demonstrate how imbalanced RP stoichiometry disrupts developmental programs, providing crucial mechanistic insights into DBAS pathogenesis and the basis for its clinical heterogeneity.</p>

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RPS19 and RPL5 haploinsufficient models reveal divergent ribosomal subunit controls of fetal hematopoiesis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月8日

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  • Yuefeng Tang,
  • Te Ling,
  • Rashid Mehmood,
  • Alexis Bertrand,
  • Julien Papoin,
  • Mushran Khan,
  • Riaz Rao,
  • Jianing Xu,
  • Vincent Schulz,
  • James Palis,
  • Laurie A. Steiner,
  • Betsy J. Barnes,
  • Yong-Rui Zou,
  • Philippe Marambaud,
  • Robert A. J. Signer,
  • Irene Roberts,
  • Deena Iskander,
  • Leonard I. Zon,
  • Senthil Velan Bhoopalan,
  • Mitchell J. Weiss,
  • Jeffrey M. Lipton,
  • Patrick G. Gallagher,
  • Narla Mohandas,
  • Naomi Taylor,
  • Sébastien Durand,
  • John Crispino,
  • Lionel Blanc

摘要

Diamond Blackfan anemia syndrome (DBAS) is a congenital ribosomopathy caused by haploinsufficiency of ribosomal proteins (RPs), but how RP stoichiometry and activity regulates erythroid development remains enigmatic. Using in vivo models, we uncover divergent functions for the small and large ribosomal subunit proteins RPS19 and RPL5 in fetal hematopoiesis. While RPL5 haploinsufficiency causes hematopoietic stem and progenitor cell (HSPC) accumulation and prenatal lethality via p53-mediated ferroptosis of mature erythroid progenitors, RPS19 haploinsufficiency leads to HSPC depletion and impaired erythroid expansion through p53-dependent apoptosis. The latter is accompanied by translational and transcriptional dysregulation, including the upregulation of RUNX1, which is also observed in RPS- haploinsufficient DBAS patients. Importantly, Runx1 deletion in RPS19-haploinsufficient mice partially rescues HSPC numbers. These findings reveal subunit-specific RP functions in controlling fetal hematopoiesis and demonstrate how imbalanced RP stoichiometry disrupts developmental programs, providing crucial mechanistic insights into DBAS pathogenesis and the basis for its clinical heterogeneity.