Language
English
Publication Date
7-23-2026
Journal
Blood
DOI
10.1182/blood.2025032207
PMID
41915769
PMCID
PMC13487487
PubMedCentral® Posted Date
4-2-2026
PubMedCentral® Full Text Version
Post-print
Abstract
Innate immunity is increasingly recognized as a driver of neurodegeneration, although pathogenic mechanisms are incompletely understood. Langerhans cell histiocytosis (LCH) is an inflammatory myeloid neoplastic disorder caused by activating somatic mutations in MAPK pathway genes, most commonly BRAFV600E, in myeloid precursors. A subset of patients with LCH develop progressive neurodegeneration (LCH-ND). We generated a human induced pluripotent stem cell (iPSC) model from patients with somatic hematologic mosaicism for BRAFV600E. Brain macrophages/microglia from LCH iPSCs exhibit unique disease-specific pathogenic features. Stepwise differentiation identified hematopoietic progenitors as hyperproliferative, whereas brain macrophages were apoptosis resistant. Through application of cerebral organoids and a humanized murine xenotransplantation model, we identify marked heterogeneity of differentiation potential within clonal BRAFV600E lines in vivo. This model phenocopied human-specific phenotypes, including dense basal ganglia foci of abnormal macrophages, marked neurodegeneration with astrogliosis, and progressive ataxia. This approach will allow for preclinical testing of therapeutics for LCH-ND.
Keywords
Humans, Animals, Mice, Induced Pluripotent Stem Cells, Phenotype, Macrophages, Cell Differentiation, Disease Models, Animal, Microglia, Brain, Neurodegenerative Diseases
Published Open-Access
yes
Recommended Citation
Rajamanickam, Shivakumar; Trescott, Samantha; Mak, Samantha; et al., "Pathogenic Myeloid Phenotypes Drive Disease Pathology in a Novel Human Neurohistiocytosis Model" (2026). Faculty, Staff and Students Publications. 7940.
https://digitalcommons.library.tmc.edu/baylor_docs/7940
Graphical Abstract