Failure of metabolic checkpoint control during late-stage granulopoiesis drives neutropenia in reticular dysgenesis.

ABSTRACT:

Abstract

Cellular metabolism is highly dynamic during hematopoiesis, yet the regulatory networks that maintain metabolic homeostasis during differentiation are incompletely understood. Herein, we have studied the grave immunodeficiency syndrome reticular dysgenesis caused by loss of mitochondrial adenylate kinase 2 (AK2) function. By coupling single-cell transcriptomics in samples from patients with reticular dysgenesis with a CRISPR model of this disorder in primary human hematopoietic stem cells, we found that the consequences of AK2 deficiency for the hematopoietic system are contingent on the effective engagement of metabolic checkpoints. In hematopoietic stem and progenitor cells, including early granulocyte precursors, AK2 deficiency reduced mechanistic target of rapamycin (m

SUBMITTER: Wang W 

PROVIDER: S-EPMC11830988 | biostudies-literature | 2024 Dec

REPOSITORIES: biostudies-literature