Dissecting ELANE neutropenia pathogenicity by human HSC gene editing

Rao, Shuquan; Yao, Yao; Brito, Josias Soares de; Yao, Qiuming; Shen, Anne H.; Watkinson, Ruth E.; Kennedy, Alyssa L.; Coyne, Steven; Ren, Chunyan; Zeng, Jing; Serbin, Anna Victoria; Studer, Sabine; Ballotti, Kaitlyn; Harris, Chad E.; Luk, Kevin; Stevens, Christian S.; Armant, Myriam; Pinello, Luca; Wolfe, Scot A.; Chiarle, Roberto; Shimamura, Akiko; Lee, Benhur; Newburger, Peter E.; Bauer, Daniel E.

doi:10.1016/j.stem.2020.12.015

Cited by 36 publications

(26 citation statements)

References 58 publications

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“…An attempt to link genotype with the risk of infections was unsuccessful, regardless of the genotype group, the exon number or the functional consequences of the variant. This clinical finding appeared to be in contradiction with the recent observation of association between genotype and progenitor cells culture 24 . In the present study, only the p.Gly214Arg variant was associated with a very high risk of infections in univariate analysis; but it is quite rare (seven cases, 5%) and it was not retained by the multivariate analysis, in contrast with previously published data suggesting that it was specific to a high risk of infection 25 …”

Section: Discussioncontrasting

confidence: 99%

“…This clinical finding appeared to be in contradiction with the recent observation of association between genotype and progenitor cells culture. 24 In the present study, only the p.Gly214Arg variant was associated with a very high risk of infections in univariate analysis; but it is quite rare (seven cases, 5%) and it was not retained by the multivariate analysis, in contrast with previously published data suggesting that it was specific to a high risk of infection. 25 The CyN and SCN subcategories appeared to offer a clear distinction concerning the risk of infection.…”

Section: Discussioncontrasting

confidence: 93%

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Recurrent bacterial infections, but not fungal infections, characterise patients with ELANE‐related neutropenia: a French Severe Chronic Neutropenia Registry study

et al. 2021

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Among 143 patients with elastase, neutrophil-expressed (ELANE)-related neutropenia enrolled in the French Severe Chronic Neutropenia Registry, 94 were classified as having severe chronic neutropenia (SCN) and 49 with cyclic neutropenia (CyN). Their infectious episodes were classified as severe, mild or oral, and analysed according to their natural occurrence without granulocyte-colony stimulating factor (G-CSF), on G-CSF, after myelodysplasia/acute leukaemia or after haematopoietic stem-cell transplantation. During the disease's natural history period (without G-CSF; 1913 person-years), 302, 957 and 754 severe, mild and oral infectious events, respectively, occurred. Among severe infections, cellulitis (48%) and pneumonia (38%) were the most common. Only 38% of episodes were microbiologically documented. The most frequent pathogens were Staphylococcus aureus (37Á4%), Escherichia coli (20%) and Pseudomonas aeruginosa (16%), while fungal infections accounted for 1%. Profound neutropenia (<200/ mm 3 ), high lymphocyte count (>3000/mm 3 ) and neutropenia subtype were associated with high risk of infection. Only the p.Gly214Arg variant (5% of the patients) was associated with infections but not the overall genotype. The first year of life was associated with the highest infection risk throughout life. G-CSF therapy achieved lower ratios of serious or oral infectious event numbers per period but was less protective for patients requiring >10 µg/kg/day. Infections had permanent consequences in 33% of patients, most frequently edentulism.

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Section: Discussioncontrasting

confidence: 99%

Section: Discussioncontrasting

confidence: 93%

Recurrent bacterial infections, but not fungal infections, characterise patients with ELANE‐related neutropenia: a French Severe Chronic Neutropenia Registry study

et al. 2021

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“…Moreover, the group headed by Daniel E. Bauer confirmed, that complete loss of NE is not associated with SCN using a new approach of ELANE gene edition within early exons, which elicited nonsense-mediated decay (NMD). They found that -1 frame insertions or deletions that produce premature termination codons escaped from NMD and were responsible for neutrophil maturation arrest, whereas -2 frame indels are tied with translation repression and neutrophil maturation (48). Those findings may be useful in therapeutic gene editing of human HSPC that trigger NMD and can restore normal neutrophil production, at the same time lay the groundwork for a new and universal therapeutic strategy for ELANEmutant SCN.…”

Section: Crispr/cas9 Gene Editingmentioning

confidence: 96%

“…Mutations introducing premature termination codons (PTCs) upstream of the 50 th nucleotide position in early exons of ELANE (1-4 exons) trigger NMDthe mechanism that eliminates defective mRNA transcripts and prevents truncated protein translations. In contrast, the mutation downstream of the 50 th nucleotide position within a late exon (4 th and 5 th ) of ELANE avoids NMD, thus, produces defective NE that impairs neutrophil maturation and manifests as severe neutropenia (48). It is consistent with previous observations in neutropenic patients, exons 4 and 5 are enriched in nonsense and frameshift mutations, which result in disruption of the disulphide bond domain in C-terminus of elastase that is essential for its correct intracellular localization (39,43,49).…”

Section: Elane Mutationsmentioning

confidence: 99%

Neutrophil Elastase Defects in Congenital Neutropenia

et al. 2021

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Severe congenital neutropenia (SCN) is a rare hematological condition with heterogenous genetic background. Neutrophil elastase (NE) encoded by ELANE gene is mutated in over half of the SCN cases. The role of NE defects in myelocytes maturation arrest in bone marrow is widely investigated; however, the mechanism underlying this phenomenon has still remained unclear. In this review, we sum up the studies exploring mechanisms of neutrophil deficiency, biological role of NE in neutrophil and the effects of ELANE mutation and neutropenia pathogenesis. We also explain the hypotheses presented so far and summarize options of neutropenia therapy.

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“…This is particularly challenging in ELANE-SCN, given the wide variety of mutations. To cope with this, one strategy aims at deleting the mutant ELANE allele accepting that the wild-type allele will also be deleted, resulting in complete loss of NE expression [ 55 , 56 ▪▪ ]. This is considered acceptable given that patients suffering from Papillon-Lefevre syndrome, who lack functional NE and other neutrophil serine proteases, present with relatively mild symptoms [ 57 ].…”

Section: Development Of New Treatment Strategiesmentioning

confidence: 99%

Congenital neutropenia: disease models guiding new treatment strategies

Touw¹

2021

Current Opinion in Hematology

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Purpose of review Myeloid diseases are often characterized by a disturbed regulation of myeloid cell proliferation, survival, and maturation. This may either result in a severe paucity of functional neutrophils (neutropenia), an excess production of mature cells (myeloproliferative disorders) or in clonal expansions of dysplastic or immature myeloid cells (myelodysplasia and acute myeloid leukemia). Although these conditions can be regarded as separate entities, caused by the accumulation of distinct sets of somatic gene mutations, it becomes increasingly clear that they may also evolve as the prime consequence of a congenital defect resulting in severe neutropenia. Prominent examples of such conditions include the genetically heterogeneous forms of severe congenital neutropenia (SCN) and Shwachman-Diamond Syndrome. CSF3 treatment is a successful therapy to alleviate neutropenia in the majority of these patients but does not cure the disease nor does it prevent malignant transformation. Allogeneic stem cell transplantation is currently the only therapeutic option to cure SCN, but is relatively cumbersome, e.g., hampered by treatment-related mortality and donor availability. Hence, there is a need for new therapeutic approaches. Recent findings Developments in disease modeling, amongst others based on induced pluripotent stem cell and CRISPR/Cas9 based gene-editing technologies, have created new insights in disease biology and possibilities for treatment. In addition, they are fueling expectations for advanced disease monitoring to prevent malignant transformation. Summary This review highlights the recent progress made in SCN disease modeling and discusses the challenges that are still ahead of us to gain a better understanding of the biological heterogeneity of the disease and its consequences for patient care.

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Dissecting ELANE neutropenia pathogenicity by human HSC gene editing

Cited by 36 publications

References 58 publications

Recurrent bacterial infections, but not fungal infections, characterise patients with ELANE‐related neutropenia: a French Severe Chronic Neutropenia Registry study

Recurrent bacterial infections, but not fungal infections, characterise patients with ELANE‐related neutropenia: a French Severe Chronic Neutropenia Registry study

Neutrophil Elastase Defects in Congenital Neutropenia

Congenital neutropenia: disease models guiding new treatment strategies

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