TY - JOUR
T1 - PML-controlled responses in severe congenital neutropenia with ELANE-misfolding mutations
AU - Olofsen, Patricia A.
AU - Bosch, Dennis A.
AU - Roovers, Onno
AU - van Strien, Paulina M.H.
AU - de Looper, Hans W.J.
AU - Hoogenboezem, Remco M.
AU - Barnhoorn, Sander
AU - Mastroberardino, Pier G.
AU - Ghazvini, Mehrnaz
AU - van der Velden, Vincent H.J.
AU - Bindels, Eric M.J.
AU - de Pater, Emma M.
AU - Touw, Ivo P.
N1 - Publisher Copyright:
© 2021 by The American Society of Hematology
PY - 2021/2/9
Y1 - 2021/2/9
N2 - Mutations in ELANE cause severe congenital neutropenia (SCN), but how they affect neutrophil production and contribute to leukemia predisposition is unknown. Neutropenia is alleviated by CSF3 (granulocyte colony-stimulating factor) therapy in most cases, but dose requirements vary between patients. Here, we show that CD341CD451 hematopoietic progenitor cells (HPCs) derived from induced pluripotent stem cell lines from patients with SCN that have mutations in ELANE (n 5 2) or HAX1 (n 5 1) display elevated levels of reactive oxygen species (ROS) relative to normal iPSC-derived HPCs. In patients with ELANE mutations causing misfolding of the neutrophil elastase (NE) protein, HPCs contained elevated numbers of promyelocyte leukemia protein nuclear bodies, a hallmark of acute oxidative stress. This was confirmed in primary bone marrow cells from 3 additional patients with ELANE-mutant SCN. Apart from responding to elevated ROS levels, PML controlled the metabolic state of these ELANE-mutant HPCs as well as the expression of ELANE, suggestive of a feed-forward mechanism of disease development. Both PML deletion and correction of the ELANE mutation restored CSF3 responses of these ELANE-mutant HPCs. These findings suggest that PML plays a crucial role in the disease course of ELANE-SCN characterized by NE misfolding, with potential implications for CSF3 therapy.
AB - Mutations in ELANE cause severe congenital neutropenia (SCN), but how they affect neutrophil production and contribute to leukemia predisposition is unknown. Neutropenia is alleviated by CSF3 (granulocyte colony-stimulating factor) therapy in most cases, but dose requirements vary between patients. Here, we show that CD341CD451 hematopoietic progenitor cells (HPCs) derived from induced pluripotent stem cell lines from patients with SCN that have mutations in ELANE (n 5 2) or HAX1 (n 5 1) display elevated levels of reactive oxygen species (ROS) relative to normal iPSC-derived HPCs. In patients with ELANE mutations causing misfolding of the neutrophil elastase (NE) protein, HPCs contained elevated numbers of promyelocyte leukemia protein nuclear bodies, a hallmark of acute oxidative stress. This was confirmed in primary bone marrow cells from 3 additional patients with ELANE-mutant SCN. Apart from responding to elevated ROS levels, PML controlled the metabolic state of these ELANE-mutant HPCs as well as the expression of ELANE, suggestive of a feed-forward mechanism of disease development. Both PML deletion and correction of the ELANE mutation restored CSF3 responses of these ELANE-mutant HPCs. These findings suggest that PML plays a crucial role in the disease course of ELANE-SCN characterized by NE misfolding, with potential implications for CSF3 therapy.
UR - http://www.scopus.com/inward/record.url?scp=85101856555&partnerID=8YFLogxK
U2 - 10.1182/bloodadvances.2020003214
DO - 10.1182/bloodadvances.2020003214
M3 - Article
C2 - 33560392
AN - SCOPUS:85101856555
SN - 2473-9529
VL - 5
SP - 775
EP - 786
JO - Blood Advances
JF - Blood Advances
IS - 3
ER -