Differential transcriptional control of hematopoiesis in congenital and cyclic neutropenia patients harboring <i>ELANE</i> mutations
Alexander Zeidler,
Natalia Borbaran-Bravo,
Benjamin Dannenmann,
Malte Ritter,
Masoud Nasri,
Maksim Klimiankou,
Sergey Kandabarau,
Azadeh Zahabi,
Josef König,
Cornelia Zeidler,
Julia Skokowa,
Karl Welte
Affiliations
Alexander Zeidler
Department of Oncology, Hematology, Clinical Immunology, and Rheumatology, University Hospital Tuebingen, Tuebingen
Natalia Borbaran-Bravo
Department of Oncology, Hematology, Clinical Immunology, and Rheumatology, University Hospital Tuebingen, Tuebingen
Benjamin Dannenmann
Department of Oncology, Hematology, Clinical Immunology, and Rheumatology, University Hospital Tuebingen, Tuebingen
Malte Ritter
Department of Oncology, Hematology, Clinical Immunology, and Rheumatology, University Hospital Tuebingen, Tuebingen
Masoud Nasri
Department of Oncology, Hematology, Clinical Immunology, and Rheumatology, University Hospital Tuebingen, Tuebingen
Maksim Klimiankou
Department of Oncology, Hematology, Clinical Immunology, and Rheumatology, University Hospital Tuebingen, Tuebingen
Sergey Kandabarau
Department of Oncology, Hematology, Clinical Immunology, and Rheumatology, University Hospital Tuebingen, Tuebingen
Azadeh Zahabi
Department of Oncology, Hematology, Clinical Immunology, and Rheumatology, University Hospital Tuebingen, Tuebingen
Josef König
Hematology and Oncology, Ordensklinikum Elisabethinen, Linz, Austria
Cornelia Zeidler
Department of Oncology, Hematology, Immunology and Bone Marrow Transplantation, Hannover Medical School, Hannover
Julia Skokowa
Department of Oncology, Hematology, Clinical Immunology, and Rheumatology, University Hospital Tuebingen, Tuebingen
Karl Welte
Department of Oncology, Hematology, Clinical Immunology, and Rheumatology, University Hospital Tuebingen, Tuebingen, Germany; Department of Pediatric Hematology and Oncology, University Children’s Hospital Tuebingen, Tuebingen
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.
