ELANE mutant–specific activation of different UPR pathways in congenital neutropenia

Nustede, R.; Klimiankou, Maksim; Klimenkova, Olga; Kuznetsova, I. A.; Zeidler, Cornelia; Welte, Karl; Skokowa, Julia

doi:10.1111/bjh.13823

Cited by 33 publications

(31 citation statements)

References 22 publications

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“…Also, a neutropenia-associated ELANE mutation that disrupts the translational start generates a shorter form of neutrophil elastase, which leads to aberrant localization of the mutated protein 48 . Intracellular accumulation and mislocalization of the mutant neutrophil elastase induces endoplasmic reticulum (ER) stress and activates the unfolded protein response (UPR) 49-52 , leading to increased apoptosis associated with up-regulation of the master ER chaperone 78 kDa glucose-regulated protein (GRP-78), XBP1 mRNA splicing and activation of ATF6 49-52 . The magnitude of UPR activation varies with different ELANE mutations 49-52 .…”

Section: Mechanisms/pathophysiologymentioning

confidence: 99%

“…Intracellular accumulation and mislocalization of the mutant neutrophil elastase induces endoplasmic reticulum (ER) stress and activates the unfolded protein response (UPR) 49-52 , leading to increased apoptosis associated with up-regulation of the master ER chaperone 78 kDa glucose-regulated protein (GRP-78), XBP1 mRNA splicing and activation of ATF6 49-52 . The magnitude of UPR activation varies with different ELANE mutations 49-52 . Interestingly, drastically diminished levels of ELANE mRNA in promyelocytes and neutrophil elastase in plasma of patients with severe congenital neutropenia have been reported 53,54 , a finding that questions how these low levels of mutated protein could induce the UPR.…”

Section: Mechanisms/pathophysiologymentioning

confidence: 99%

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Severe congenital neutropenias

Skokowa

Dale

Touw

et al. 2017

Nat Rev Dis Primers

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274

318

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Severe congenital neutropenias are a heterogeneous group of rare haematological diseases that are characterized by impaired maturation of neutrophil granulocytes. Patients with severe congenital neutropenia are prone to recurrent, often life-threatening infections beginning in their first months of life. The most frequent pathogenetic defects are autosomal dominant mutations in ELANE, which encodes neutrophil elastase, and autosomal recessive mutations in HAX1, whose product contributes to the activation of the granulocyte-colony stimulating factor (G-CSF) signalling pathway. The pathophysiological mechanisms of these conditions are the object of extensive research and are not fully understood. Furthermore, severe congenital neutropenias may predispose to myelodysplastic syndromes or acute myeloid leukaemia. Molecular events in the malignant progression include acquired mutations in CSF3R (encoding G-CSF receptor) and subsequently in other leukaemia-associated genes (such as RUNX1) in a majority of patients. Diagnosis is based on clinical manifestations, blood neutrophil count, bone marrow examination, and genetic and immunological analyses. Daily subcutaneous G-CSF administration is the treatment of choice and leads to a substantial increase in blood neutrophils count, reduction of infections and drastic improvement of quality of life. Haematopoietic stem cell transplantation is the alternative treatment. Regular clinical assessments (including yearly bone marrow examinations) to monitor treatment course and detect chromosomal abnormalities (e.g. trisomy 21, monosomy 7) as well as somatic pre-leukaemic mutations are recommended.

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Section: Mechanisms/pathophysiologymentioning

confidence: 99%

Section: Mechanisms/pathophysiologymentioning

confidence: 99%

Severe congenital neutropenias

Skokowa

Dale

Touw

et al. 2017

Nat Rev Dis Primers

Self Cite

274

318

View full text Add to dashboard Cite

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“…18 However, not all ELANE mutations induce UPR, and moreover, different mutations differentially affect the 3 branches of the UPR. 19 These differences might be explained by the abnormal accumulation of the protein in different intracellular compartments.…”

Section: Monogenic Disorders and Syndromesmentioning

confidence: 99%

New monogenic disorders identify more pathways to neutropenia: from the clinic to next-generation sequencing

Corey

Oyarbide

2017

Hematology

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Neutrophils are the most common type of leukocyte in human circulating blood and constitute one of the chief mediators for innate immunity. Defined as a reduction from a normal distribution of values, neutropenia results from a number of congenital and acquired conditions. Neutropenia may be insignificant, temporary, or associated with a chronic condition with or without a vulnerability to life-threatening infections. As an inherited bone marrow failure syndrome, neutropenia may be associated with transformation to myeloid malignancy. Recognition of an inherited bone marrow failure syndrome may be delayed into adulthood. The list of monogenic neutropenia disorders is growing, heterogeneous, and bewildering. Furthermore, greater knowledge of immune-mediated and drug-related causes makes the diagnosis and management of neutropenia challenging. Recognition of syndromic presentations and especially the introduction of next-generation sequencing are improving the accuracy and expediency of diagnosis as well as their clinical management. Furthermore, identification of monogenic neutropenia disorders is shedding light on the molecular mechanisms of granulopoiesis and myeloid malignancies.

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“…Also, a neutropenia-associated ELANE mutation that disrupts the translational start generates a shorter form of neutrophil elastase, which leads to aberrant localization of the mutated protein 48 . Intracellular accumulation and mislocalization of the mutant neutrophil elastase induces endoplasmic reticulum (ER) stress and activates the unfolded protein response (UPR) [49][50][51][52] , leading to increased apoptosis associated with up-regulation of the master ER chaperone 78 kDa glucose-regulated protein (GRP-78), XBP1 mRNA splicing and activation of ATF6 [49][50][51][52] . The magnitude of UPR activation varies with different ELANE mutations [49][50][51][52] .…”

Section: Pathological Mechanismsmentioning

confidence: 99%

“…Intracellular accumulation and mislocalization of the mutant neutrophil elastase induces endoplasmic reticulum (ER) stress and activates the unfolded protein response (UPR) [49][50][51][52] , leading to increased apoptosis associated with up-regulation of the master ER chaperone 78 kDa glucose-regulated protein (GRP-78), XBP1 mRNA splicing and activation of ATF6 [49][50][51][52] . The magnitude of UPR activation varies with different ELANE mutations [49][50][51][52] . Interestingly, drastically diminished levels of ELANE mRNA in promyelocytes and neutrophil elastase in plasma of patients with severe congenital neutropenia have been reported 53,54 , a finding that questions how these low levels of mutated protein could induce the UPR.…”

Section: Pathological Mechanismsmentioning

confidence: 99%

Severe congenital neutropenias

2017

Nat Rev Dis Primers

View full text Add to dashboard Cite

Severe congenital neutropenias are a heterogeneous group of rare haematological diseases that are characterized by impaired maturation of neutrophil granulocytes. Patients with severe congenital neutropenia are prone to recurrent, often life-threatening infections beginning in their first months of life. The most frequent pathogenetic defects are autosomal dominant mutations in ELANE, which encodes neutrophil elastase, and autosomal recessive mutations in HAX1, whose product contributes to the activation of the granulocyte-colony stimulating factor (G-CSF) signalling pathway. The pathophysiological mechanisms of these conditions are the object of extensive research and are not fully understood. Furthermore, severe congenital neutropenias may predispose to myelodysplastic syndromes or acute myeloid leukaemia. Molecular events in the malignant progression include acquired mutations in CSF3R (encoding G-CSF receptor) and subsequently in other leukaemia-associated genes (such as RUNX1) in a majority of patients.Diagnosis is based on clinical manifestations, blood neutrophil count, bone marrow examination, and genetic and immunological analyses. Daily subcutaneous G-CSF administration is the treatment of choice and leads to a substantial increase in blood neutrophils count, reduction of infections and drastic improvement of quality of life. Haematopoietic stem cell transplantation is the alternative treatment. Regular clinical assessments (including yearly bone marrow examinations) to monitor treatment course and detect chromosomal abnormalities (e.g. trisomy 21, monosomy 7) as well as somatic pre-leukaemic mutations are recommended. Graphical abstractCorrespondence to: K.W., karl.welte@med.uni-tuebingen.de.

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ELANE mutant–specific activation of different UPR pathways in congenital neutropenia

Cited by 33 publications

References 22 publications

Severe congenital neutropenias

Severe congenital neutropenias

New monogenic disorders identify more pathways to neutropenia: from the clinic to next-generation sequencing

Severe congenital neutropenias

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