Pathogenesis of ELANE-mutant severe neutropenia revealed by induced pluripotent stem cells

Nayak, Ramesh C.; Trump, Lisa; Aronow, Bruce J.; Myers, Kasiani C.; Mehta, Parinda A.; Kalfa, Theodosia A.; Wellendorf, Ashley M; Valencia, C. Alexander; Paddison, Patrick J.; Horwitz, Marshall S.; Grimes, H. Leighton; Lutzko, Carolyn; Cancelas, José A.

doi:10.1172/jci80924

Cited by 71 publications

(67 citation statements)

References 58 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Although whole genome sequencing is required to fully exclude off-target cleavage of the Cas9 endonuclease, [57][58][59] careful selection of the sgRNAs and the subsequent data indicate that our system provides genetically defined conditions to investigate the net effect of the HAX1 W44X mutation, as it was previously shown for ELANE mutations in SCN and X-linked chronic granulomatous disease. 60,61 These isogenic iPSCs can facilitate drug or toxicity screenings to find the most advantageous therapies in this rare disease; furthermore, they create an ideal platform for the development of improved therapy in SCN.…”

Section: Discussionmentioning

confidence: 99%

Gene correction of HAX1 reversed Kostmann disease phenotype in patient-specific induced pluripotent stem cells

et al. 2017

View full text Add to dashboard Cite

Key Points• HAX1W44X -iPSCs recapitulate Kostmann disease phenotype in vitro.• Genetic in situ correction of iPSCs reveals a dysregulated HAX1 and HCLS1-centered interaction network in Kostmann disease. nonsense mutation. Targeted correction of the HAX1 mutation using the CRISPR-Cas9 system and homologous recombination rescued neutrophil differentiation and reestablished an HAX1 and HCLS1-centered transcription network in immature myeloid progenitors, which is involved in the regulation of apoptosis, apoptotic mitochondrial changes, and myeloid differentiation. These findings made in isogenic iPSC-derived myeloid cells highlight the complex transcriptional changes underlying Kostmann disease. Thus, weshow that patient-derived HAX1 W44X

show abstract

Section: Discussionmentioning

confidence: 99%

Gene correction of HAX1 reversed Kostmann disease phenotype in patient-specific induced pluripotent stem cells

et al. 2017

View full text Add to dashboard Cite

show abstract

“…These results may explain why G-CSFR d715, but not the WT G-CSFR, is capable of protecting myeloid cells from apoptosis induced by NE G185R. Notably, it has been shown that forced expression of a constitutively active AKT rescued apoptosis induced by SCNassociated NE mutants in induced pluripotent stem cell-derived myeloid precursor cells (11). It is also of note that STAT5 proteins, including STAT5A and STAT5B, have been shown to be associated with ER and that siRNA-mediated knockdown of STAT5A/B resulted in increased accumulation of GRP78 in ER (47).…”

Section: Csf3r and Elane Mutations In Scn/amlmentioning

confidence: 95%

A Truncated Granulocyte Colony-stimulating Factor Receptor (G-CSFR) Inhibits Apoptosis Induced by Neutrophil Elastase G185R Mutant: IMPLICATION FOR UNDERSTANDING CSF3R GENE MUTATIONS IN SEVERE CONGENITAL NEUTROPENIA

Qiu

Zhang

et al. 2017

Journal of Biological Chemistry

View full text Add to dashboard Cite

Edited by Xiao-Fan WangMutations in ELANE encoding neutrophil elastase (NE) have been identified in the majority of patients with severe congenital neutropenia (SCN). The NE mutants have been shown to activate unfolded protein response and induce premature apoptosis in myeloid cells. Patients with SCN are predisposed to acute myeloid leukemia (AML), and progression from SCN to AML is accompanied by mutations in CSF3R encoding the granulocyte colony-stimulating factor receptor (G-CSFR) in ϳ80% of patients. The mutations result in the expression of C-terminally truncated G-CSFRs that promote strong cell proliferation and survival. It is unknown why the CSF3R mutations, which are rare in de novo AML, are so prevalent in SCN/AML. We show here that a G-CSFR mutant, d715, derived from an SCN patient inhibited G-CSF-induced expression of NE in a dominant negative manner. Furthermore, G-CSFR d715 suppressed unfolded protein response and apoptosis induced by an SCN-derived NE mutant, which was associated with sustained activation of AKT and STAT5, and augmented expression of BCL-XL. Thus, the truncated G-CSFRs associated with SCN/AML may protect myeloid precursor cells from apoptosis induced by the NE mutants. We propose that acquisition of CSF3R mutations may represent a mechanism by which myeloid precursor cells carrying the ELANE mutations evade the proapoptotic activity of the NE mutants in SCN patients.

show abstract

“…Author Manuscript Author Manuscript iPSCs have been generated from somatic cells of patients with either ELANE or HAX1 mutations [129][130][131] . With the establishment of efficient protocols for in vitro haematopoietic and myeloid differentiation of iPSCs cells 132,133 , these cells could be used as an experimental model to study the pathophysiology of disease.…”

Section: Author Manuscript Author Manuscriptmentioning

confidence: 99%

“…With the establishment of efficient protocols for in vitro haematopoietic and myeloid differentiation of iPSCs cells 132,133 , these cells could be used as an experimental model to study the pathophysiology of disease. Successful restoration of defective granulopoiesis in vitro has been achieved by lentivirus-or CRISPR/Cas9-based correction of mutated ELANE or HAX1 in iPSCs [129][130][131] . Thus, correction of the underlying gene mutation ex vivo with the CRISPR/Cas9 technology followed by autologous stem cell transplantation is a promising future therapeutic option.…”

Section: Author Manuscript Author Manuscriptmentioning

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.

show abstract

Pathogenesis of ELANE-mutant severe neutropenia revealed by induced pluripotent stem cells

Cited by 71 publications

References 58 publications

Gene correction of HAX1 reversed Kostmann disease phenotype in patient-specific induced pluripotent stem cells

Gene correction of HAX1 reversed Kostmann disease phenotype in patient-specific induced pluripotent stem cells

A Truncated Granulocyte Colony-stimulating Factor Receptor (G-CSFR) Inhibits Apoptosis Induced by Neutrophil Elastase G185R Mutant: IMPLICATION FOR UNDERSTANDING CSF3R GENE MUTATIONS IN SEVERE CONGENITAL NEUTROPENIA

Severe congenital neutropenias

Contact Info

Product

Resources

About