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New insights into the pathomechanism of cyclic neutropenia
Author(s) -
Mir Perihan,
Klimiankou Maksim,
Findik Betuel,
Hähnel Karin,
MellorHeineke Sabine,
Zeidler Cornelia,
Skokowa Julia,
Welte Karl
Publication year - 2020
Publication title -
annals of the new york academy of sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.712
H-Index - 248
eISSN - 1749-6632
pISSN - 0077-8923
DOI - 10.1111/nyas.14309
Subject(s) - cyclic neutropenia , haematopoiesis , unfolded protein response , progenitor cell , bone marrow , immunology , biology , granulocyte , stem cell , microbiology and biotechnology , neutropenia , granulocyte colony stimulating factor , endoplasmic reticulum , cancer research , genetics , chemotherapy
Cyclic neutropenia (CyN) is a hematologic disorder in which peripheral blood absolute neutrophil counts (ANCs) show cycles of approximately 21‐day intervals. The majority of CyN patients harbor ELANE mutations, but the mechanism of ANC cycling is unclear. We performed analysis of bone marrow (BM) subpopulations in CyN patients at the peak and the nadir of the ANC cycle and detected high proportions of BM hematopoietic stem cells (HSCs) and hematopoietic stem and progenitor cells (HSPCs) at the nadir of the ANC cycle, as compared with the peak. BM HSPCs produced fewer granulocyte colony‐forming unit colonies at the ANC peak. To investigate the mechanism of cycling, we found that mRNA expression levels of ELANE and unfolded protein response (UPR)–related genes ( ATF6 , BiP ( HSPA5 ), CHOP ( DDIT3 ), and PERK ( EIF2AK3 )) were elevated, but antiapoptotic genes ( Bcl‐2 ( BCL2 ) and bcl‐xL ( BCL2L1 )) were reduced in CD34 + cells tested at the ANC nadir. Moreover, HSPCs revealed increased levels of reactive oxygen species and gH2AX at the ANC nadir. We suggest that in CyN patients, some HSPCs escape the UPR‐induced endoplasmic reticulum (ER) stress and proliferate in response to granulocyte colony‐stimulating factor (G‐CSF) to a certain threshold at which UPR again affects the majority of HSPCs. There is a cyclic balance between ER stress–induced apoptosis of HSPCs and compensatory G‐CSF–stimulated HSPC proliferation followed by granulocytic differentiation.