Molecular mechanisms of aberrant neutrophil differentiation in glycogen storage disease type Ib

• Published in: Cellular and molecular life sciences : CMLS 2022-05, Vol.79 (5), p.246-246, Article 246
• Main Authors: Sim, Sang Wan, Jang, Yuyeon, Park, Tae Sub, Park, Byung-Chul, Lee, Young Mok, Jun, Hyun Sik
• Format: Article
• Language: English
• Subjects: Animals; Antiporters - genetics; Antiporters - metabolism; Apoptosis; Biochemistry; Biomedical and Life Sciences; Biomedicine; Bone marrow; Cell Biology; Cell differentiation; Cell lines; Cells (biology); CRISPR; Differentiation; G6PT gene; Glucose; Glucose - metabolism; Glucose transporter; Glycogen; Glycogen Storage Disease Type I - complications; Glycogen Storage Disease Type I - genetics; Glycogen Storage Disease Type I - metabolism; Glycogens; Homeostasis; Leukocytes (neutrophilic); Life Sciences; Lipid metabolism; Lipids; Mice; Molecular modelling; Neutropenia; Neutropenia - complications; Neutropenia - metabolism; Neutrophils; Neutrophils - metabolism; Original; Original Article; Peroxisome proliferator-activated receptors; Phosphate transporter; PPAR gamma - genetics; PPAR gamma - metabolism; Progenitor cells; Stem cells; Storage diseases; Transcription
• ISSN: 1420-682X; 1420-9071
• DOI: 10.1007/s00018-022-04267-5

Glycogen storage disease type Ib (GSD-Ib), characterized by impaired glucose homeostasis, neutropenia, and neutrophil dysfunction, is caused by a deficiency in glucose-6-phosphate transporter (G6PT). Neutropenia in GSD-Ib has been known to result from enhanced apoptosis of neutrophils. However, it has also been raised that neutrophil maturation arrest in the bone marrow would contribute to neutropenia. We now show that G6pt −/− mice exhibit severe neutropenia and impaired neutrophil differentiation in the bone marrow. To investigate the role of G6PT in myeloid progenitor cells, the G6PT gene was mutated using CRISPR/Cas9 system, and single cell-derived G6PT −/− human promyelocyte HL-60 cell lines were established. The G6PT −/− HL-60s exhibited impaired neutrophil differentiation, which is associated with two mechanisms: (i) abnormal lipid metabolism causing a delayed metabolic reprogramming and (ii) reduced nuclear transcriptional activity of peroxisome proliferator-activated receptor-γ (PPARγ) in G6PT −/− HL-60s. In this study, we demonstrated that G6PT is essential for neutrophil differentiation of myeloid progenitor cells and regulates PPARγ activity.