Klin Padiatr 2022; 234(03): 179
DOI: 10.1055/s-0042-1748701
Abstracts

New Insights into the pathophysiology of cyclic neutropenia

A Zeidler
1   University Hospital Tübingen, Tübingen, Germany
,
B Dannenmann
1   University Hospital Tübingen, Tübingen, Germany
,
M Klimiankou
1   University Hospital Tübingen, Tübingen, Germany
,
C Zeidler
2   Medial School Hannover, Hannover, Germany
,
J Skokowa
1   University Hospital Tübingen, Tübingen, Germany
,
K Welte
1   University Hospital Tübingen, Tübingen, Germany
› Author Affiliations
 

Cyclic neutropenia (CyN) is a bone marrow failure syndrome caused by mutations in the ELANE generally with 21-day cycles of peripheral blood neutrophils. These mutations lead to the production of misfolded elastase protein and subsequent elevated unfolded protein response (UPR) in the endoplasmatic reticulum. By searching for additional molecular pathomechanisms of CyN, we identified cycle-dependent expression of CEBPA, MLL1 and their targets, the homeobox factors HOXA9 and MEIS1. At the peak of CyN, there was a 5 to 7 fold expression of these factors compared to cells from healthy controls and a high percentage of CD49f+ HSCs that escape from UPR damage since they do not express NE. This reveals a high replenishment activity of CD49f+ HSCs (escaper cells) in CyN in response to G-CSF and ensures sufficient neutrophil numbers at the following cycle. However, the newly generated and differentiated CD49f negative cells again express mutated NE and are prone to UPR-caused apoptosis requiring again asymmetric division of ELANE negative 49f+ HSC at the peak of the cycle to generate new mature HSCs.



Publication History

Article published online:
17 May 2022

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