PML-controlled responses in severe congenital neutropenia with ELANE-misfolding mutations

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Mutations in ELANE cause severe congenital neutropenia (SCN), but how they affect neutrophil production and contribute to leukemia predisposition is unknown. Neutropenia is alleviated by CSF3 (granulocyte colony-stimulating factor) therapy in most cases, but dose requirements vary between patients. Here, we show that CD341CD451 hematopoietic progenitor cells (HPCs) derived from induced pluripotent stem cell lines from patients with SCN that have mutations in ELANE (n 5 2) or HAX1 (n 5 1) display elevated levels of reactive oxygen species (ROS) relative to normal iPSC-derived HPCs. In patients with ELANE mutations causing misfolding of the neutrophil elastase (NE) protein, HPCs contained elevated numbers of promyelocyte leukemia protein nuclear bodies, a hallmark of acute oxidative stress. This was confirmed in primary bone marrow cells from 3 additional patients with ELANE-mutant SCN. Apart from responding to elevated ROS levels, PML controlled the metabolic state of these ELANE-mutant HPCs as well as the expression of ELANE, suggestive of a feed-forward mechanism of disease development. Both PML deletion and correction of the ELANE mutation restored CSF3 responses of these ELANE-mutant HPCs. These findings suggest that PML plays a crucial role in the disease course of ELANE-SCN characterized by NE misfolding, with potential implications for CSF3 therapy.

Original languageEnglish
Pages (from-to)775-786
Number of pages12
JournalBlood advances
Issue number3
Publication statusPublished - 3 Feb 2021

Bibliographical note

Funding Information:
This work was supported by grants from KWF Kankerbestrijding (EMCR 2013-5755 and EMCR 2014-6780) and the Cancer

Funding Information:
Genome Editing Center of the Erasmus MC Cancer Institute funded by the Daniel den Hoed Foundation.

Publisher Copyright:
© 2021 by The American Society of Hematology

Research programs

  • EMC OR-01


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