Truncated CSF3 receptors induce pro-inflammatory responses in severe congenital neutropenia

Patricia A. Olofsen, Dennis A. Bosch, Hans W. J. de Looper, Paulina M. H. van Strien, Remco M. Hoogenboezem, Onno Roovers, Vincent H. J. van der Velden, Eric M. J. Bindels, Emma M. De Pater, Ivo P. Touw*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Severe congenital neutropenia (SCN) patients are prone to develop myelodysplastic syndrome (MDS) or acute myeloid leukaemia (AML). Leukaemic progression of SCN is associated with the early acquisition of CSF3R mutations in haematopoietic progenitor cells (HPCs), which truncate the colony-stimulating factor 3 receptor (CSF3R). These mutant clones may arise years before MDS/AML becomes overt. Introduction and activation of CSF3R truncation mutants in normal HPCs causes a clonally dominant myeloproliferative state in mice treated with CSF3. Paradoxically, in SCN patients receiving CSF3 therapy, clonal dominance of CSF3R mutant clones usually occurs only after the acquisition of additional mutations shortly before frank MDS or AML is diagnosed. To seek an explanation for this discrepancy, we introduced a patient-derived CSF3R-truncating mutation in ELANE-SCN and HAX1-SCN derived and control induced pluripotent stem cells and compared the CSF3 responses of HPCs generated from these lines. In contrast to CSF3R-mutant control HPCs, CSF3R-mutant HPCs from SCN patients do not show increased proliferation but display elevated levels of inflammatory signalling. Thus, activation of the truncated CSF3R in SCN-HPCs does not evoke clonal outgrowth but causes a sustained pro-inflammatory state, which has ramifications for how these CSF3R mutants contribute to the leukaemic transformation of SCN.

Original languageEnglish
Pages (from-to)79-86
Number of pages8
JournalBritish Journal of Haematology
Issue number1
Publication statusE-pub ahead of print - 28 Sep 2022

Bibliographical note

Funding Information:
This work was supported by grants from KWF Kankerbestrijding (EMCR 2013‐6080 and EMCR 2014‐6780), and the Cancer Genome Editing Center of the Erasmus MC Cancer Institute funded by the Daniel den Hoed Foundation. We thank Mehrnaz Ghazvini for generation of the iPSCs.

Publisher Copyright:
© 2022 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.


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