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

Autor: Olofsen PA; Department of Hematology, Erasmus University Medical Center, Rotterdam, the Netherlands., Bosch DA; Department of Hematology, Erasmus University Medical Center, Rotterdam, the Netherlands., de Looper HWJ; Department of Hematology, Erasmus University Medical Center, Rotterdam, the Netherlands., van Strien PMH; Department of Hematology, Erasmus University Medical Center, Rotterdam, the Netherlands., Hoogenboezem RM; Department of Hematology, Erasmus University Medical Center, Rotterdam, the Netherlands., Roovers O; Department of Hematology, Erasmus University Medical Center, Rotterdam, the Netherlands., van der Velden VHJ; Department of Immunology, Erasmus University Medical Center, Rotterdam, the Netherlands., Bindels EMJ; Department of Hematology, Erasmus University Medical Center, Rotterdam, the Netherlands., De Pater EM; Department of Hematology, Erasmus University Medical Center, Rotterdam, the Netherlands., Touw IP; Department of Hematology, Erasmus University Medical Center, Rotterdam, the Netherlands.
Jazyk: angličtina
Zdroj: British journal of haematology [Br J Haematol] 2023 Jan; Vol. 200 (1), pp. 79-86. Date of Electronic Publication: 2022 Sep 28.
DOI: 10.1111/bjh.18477
Abstrakt: 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.
(© 2022 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)
Databáze: MEDLINE
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