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Differential transcriptional control of hematopoiesis in congenital and cyclic neutropenia patients harboring ELANE mutations.
- Source :
-
Haematologica [Haematologica] 2024 May 01; Vol. 109 (5), pp. 1393-1402. Date of Electronic Publication: 2024 May 01. - Publication Year :
- 2024
-
Abstract
- Mutations in the ELANE gene, encoding the neutrophil elastase (NE) protein, are responsible for most cyclic neutropenia (CyN) cases and approximately 25% of congenital neutropenia (CN) cases. In CN and in CyN, a median of 2.8% of CD34+ cells were early CD49f+ hematopoietic stem cells (eHSC) that did not express ELANE and thus escape from the unfolded protein response (UPR) caused by mutated NE. In CyN, the CD49f+ cells respond to granulocyte colony-stimulating factor (G-CSF) with a significant upregulation of the hematopoietic stem cell-specific transcription factors, C/EBPα, MLL1, HOXA9, MEIS1, and HLF during the ascending arm of the cycle, resulting in the differentiation of myeloid cells to mature neutrophils at the cycle peak. However, NE protein released by neutrophils at the cycle's peak caused a negative feedback loop on granulopoiesis through the proteolytic digestion of G-CSF. In contrast, in CN patients, CD49f+ cells failed to express mRNA levels of HSC-specific transcription factors mentioned above. Rescue of C/EBPα expression in CN restored granulopoiesis.
- Subjects :
- Humans
Gene Expression Regulation
Hematopoietic Stem Cells metabolism
Hematopoietic Stem Cells cytology
Transcription, Genetic
Granulocyte Colony-Stimulating Factor metabolism
Neutrophils metabolism
Male
Congenital Bone Marrow Failure Syndromes genetics
Congenital Bone Marrow Failure Syndromes pathology
Female
Leukocyte Elastase genetics
Leukocyte Elastase metabolism
Neutropenia congenital
Neutropenia genetics
Neutropenia metabolism
Mutation
Hematopoiesis genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1592-8721
- Volume :
- 109
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Haematologica
- Publication Type :
- Academic Journal
- Accession number :
- 37855057
- Full Text :
- https://doi.org/10.3324/haematol.2023.284033