Differential transcriptional control of hematopoiesis in congenital and cyclic neutropenia patients harboring ELANE 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

doi:10.3324/haematol.2023.284033

Differential transcriptional control of hematopoiesis in congenital and cyclic neutropenia patients harboring ELANE mutations

Haematologica. 2024 May 1;109(5):1393-1402. doi: 10.3324/haematol.2023.284033.

Affiliations

¹ Department of Oncology, Hematology, Clinical Immunology, and Rheumatology, University Hospital Tuebingen, Tuebingen.
² Hematology and Oncology, Ordensklinikum Elisabethinen, Linz, Austria.
³ Department of Oncology, Hematology, Immunology and Bone Marrow Transplantation, Hannover Medical School, Hannover.
⁴ 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. [email protected].

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Congenital Bone Marrow Failure Syndromes / genetics
Congenital Bone Marrow Failure Syndromes / pathology
Female
Gene Expression Regulation
Granulocyte Colony-Stimulating Factor / metabolism
Hematopoiesis* / genetics
Hematopoietic Stem Cells / cytology
Hematopoietic Stem Cells / metabolism
Humans
Leukocyte Elastase* / genetics
Leukocyte Elastase* / metabolism
Male
Mutation*
Neutropenia* / congenital
Neutropenia* / genetics
Neutropenia* / metabolism
Neutrophils / metabolism
Transcription, Genetic

Substances

Leukocyte Elastase
ELANE protein, human
Granulocyte Colony-Stimulating Factor

Supplementary concepts

Cyclic neutropenia

Grants and funding

Funding: This work was supported by the Intramural Fortüne program of the Medical Faculty of the UKT (to MK, AZ), Madeleine Schickedanz Kinderkrebsstiftung (to JS, KW, MK, MN), DFG (to JS, AZ), BMBF (to JS, KW, CZ, SK), and the COST Action European Network for Innovative Diagnosis and Treatment of Chronic Neutropenias (EuNet-INNOCHRON) (to KW, CZ, MK, JS). We acknowledge the support by the Open Access Publishing Fund of the University of Tübingen.