Differential Expression of C/Ebpa and Its Stem Cell-Specific Targets in Congenital Neutropenias and Cyclic Neutropenias

Abstract

Severe congenital neutropenias (CN) and cyclic neutropenias (CyN) are disorders of hematopoiesis that differ markedly in disease severity. Mutations in ELANE are considered responsible for most cases of CyN and CN. ELANE mutations lead to accelerated apoptosis of myeloid progenitor cells due to the production of misfolded elastase protein and subsequent elevated unfolded protein response (UPR). In CyN at the peak of the cycle up to 10 % of the CD34+ cells were immature CD49f+ HSC that did not express mutated ELANE and therefore escaped from UPR (escaper cells). The proliferation and differentiation of CD49f+ cells during the ascending arm of the cycle led to increased neutrophils at the peak of the cycle stimulated by G-CSF, C/EBPA, HLF, MLL1, HOXA9 and MEIS1. At the peak of the cycle, CD34+ cells comprising the high percentage of CD49f+ cells, expressed up to 8-fold more C/EBPA, MLL1, HOXA9, MEIS1, and HLF levels as compared to cells from untreated healthy controls. This ensured sufficient neutrophil numbers in CyN at the peak. However, the mutated neutrophil elastase protein released by the high numbers of neutrophils at the peak of the cycle caused negative feedback of granulopoiesis by proteolytic digestion of G-CSF. Since G-CSF was not available anymore, CD34+ cells including CD49f+ cells did not proliferate and differentiate anymore during the downward arm of the cycle leading to neutropenia. CD34+ cells from CN patients contained only low percentages of CD49f+ cells and there was defective or no expression of C/EBPA, HLF, MLL1, HOXA9, and MEIS1.