Oscillating mRNA expression of neutrophil granule proteins and preleukemic CSF3R/RUNX1 mutations in cyclic neutropenia patients

DSpace Repository


URI: http://hdl.handle.net/10900/90001
Dokumentart: Dissertation
Date: 2019-07-02
Language: English
Faculty: 4 Medizinische Fakultät
Department: Medizin
Advisor: Skokowa, Julia (Prof. Dr.)
Day of Oral Examination: 2019-03-28
DDC Classifikation: 610 - Medicine and health
Keywords: Neutrophiler Granulozyt , G-CSF , Akute myeloische Leukämie , Neutropenie , Angeborene Krankheit
Other Keywords: RUNX1
Zyklische Neutropenie
cyclic neutropenia
gene expression
neutrophil granule protein
License: Publishing license including print on demand
Order a printed copy: Print-on-Demand
Show full item record


CyN is a rare hematopoietic disorder characterized by an oscillating count of neutrophils ranging from less than 200 neutrophils per µl at the cycle nadir to a maximum of 2000 neutrophils per µl at the cycle peak in an average 21-day rhythm. At the nadir of the ANC cycle, the patients consequently suffer from multiple bacterial and fungal infections. As a subtype of SCN, which shows a constant low ANC, both phenotypes are known to be associated with mutations in ELANE. However, the pathomechanism leading to the typical ANC cycling in CyN is unclear. This work focuses on the probable influences and regulatory mechanisms that could contribute to this cycling phenomenon. A microarray run performed with an index CyN patient represented the starting point of experiments. This microarray showed cycling patterns of granule protein genes and NAMPT expressions inverse to the ANC course. To confirm these findings, the index patient’s data were verified by using qPCR. Additionally, four further CyN patients and six healthy donors served as comparison groups. While the cycling character in nine out of ten examined genes was confirmed in the index CyN patient, only three genes were cycling only slightly in the other CyN patients, among them ELANE. This inversely cycling ELANE expression, as compared to the ANC oscillations in all examined CyN patients, contributed to the hypothesis of a negative feedback regulation of neutrophil maturation. Moreover, as a reason for the difference in expression of the index patient to the others, the index patient’s additionally inherited C/EBPe mutation was discussed. This mutation could lead to the inhibition of secondary granule proteins, thus contributing, besides other variables, to the unique protein expression and the neutropenic situation in this patient. As another differentiating criterion to SCN, CyN was always described as benign and not to be associated with MDS/AML. However, in 2016, the author’s research group identified the first two CyN patients harboring the preleukemic CSF3R mutation by deep, ultradeep, and exome sequencing. One of these patients additionally acquired the RUNX1 mutation and was diagnosed with AML. With this knowledge, a prophylactic screening of CyN patients becomes particularly important.

This item appears in the following Collection(s)