page_title: Cyclic neutropenia
section_title: Causes
hierarchical_section_title: Cyclic neutropenia / Causes
caption_attribution_description: English: "A hypothesis of UPR‐induced cycling of hematopoiesis. Schematic of the relationship between peripheral blood ANC (purple line) and UPR intensity in bone marrow HSCs and progenitor cells of CyN patients"
context_page_description: Cyclic neutropenia is a rare hematologic disorder and form of congenital neutropenia that tends to occur approximately every three weeks and lasting for few days at a time due to changing rates of neutrophil production by the bone marrow. It causes a temporary condition with a low absolute neutrophil count and because the neutrophils make up the majority of circulating white blood cells it makes the body in severe risk to inflammation and infection. In comparison to severe congenital neutropenia, it responds well to treatment with granulocyte colony-stimulating factor, which increases the neutrophil count, shortens the cycle length, as well decreases the severity and frequency of infections.
context_section_description: Cyclic neutropenia (CyN), like severe congenital neutropenia (SCN), is a rare disorder. It is considered that in the general population, CyN has a frequency of one in one million. It is the result of autosomal dominant mutation in ELANE gene located on the short arm (p) of chromosome 19 (19p13.3), the gene encoding neutrophil elastase, which is also the most common cause of the SCN. It sporadically occurs as a de novo mutation variant and/or can be present among members of the same family. In the case of CyN, the mutation variants have been found to mostly cluster in intron 4 and exon 4 and 5, but were also located in intron 3, and exon 2 and 3. Some mutation variants have been found in both Cyn and SCN, which indicates they are phenotypes of the same disease with different severity.
  It is considered that the mutation causes a decrease in the "neutrophil production or excessive apoptosis (shorter half-life)" which results in a deficiency of mature neutrophils in the blood. The exact pathological mechanism is still researched, with the main hypotheses being mislocalization of ELANE or unfolded protein response (UPR) induced by mutant ELANE, however according to Mehta et al. (2016), the "UPR induction by mutant ELANE is not strong enough to promote cell death and that mutant ELANE causes SCN through an alternative mechanism". According to Garg et al. (2020), new "findings challenge the currently prevailing model that SCN results from mutant ELANE, which triggers endoplasmic reticulum stress, UPR, and apoptosis". The expression of the ELANE gene has been linked to GFI1 gene, and some considered that interaction with other genes causes the emergence and severity of one or the other phenotypic disorder. It is unclear what causes the cyclic aspect in CyN. According to Donadieu et al. (2011), the "cyclic aspect ... suggests the existence of a cryptic biological clock that regulates granulopoiesis. This putative clock might be revealed by particular mutations". Michael Mackey "postulates that the production of neutrophils is governed by long‐range stimulatory factors in a long feedback loop that has a built‐in time delay in the maturation of promyelocytes to fully differentiated neutrophils". It is also not clear what causes that the levels of secretory leucocyte protease inhibitor (SLPI), which influences the induction of the unfolded protein response (UPR), are not diminished and as such activation of UPR is absent in CyN compared to SCN, in other words, different ELANE mutations "have different effects on UPR activation, and SLPI regulates the extent of ELANE‐triggered UPR".
  According to 2020 study published in Annals of the New York Academy of Sciences about the pathomechanism of CyN, was revealed that "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", in other words, CyN is "characterized by cycling UPR activities and cycling UPR‐escaping cells". Also, the most probable reason that from the same mutation variant develops SCN and not CyN is due to more severe damage caused by UPR stress in SCN.
caption: "A hypothesis of UPR‐induced cycling of hematopoiesis. Schematic of the relationship between peripheral blood ANC (purple line) and UPR intensity in bone marrow HSCs and progenitor cells of CyN patients", per Mir et al. (2020).[19]
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