Cellular stress pathways in pediatric bone marrow failure syndromes: many roads lead to neutropenia

Abstract

The inherited bone marrow failure syndromes, like severe congenital neutropenia (SCN) and Shwachman-Diamond syndrome (SDS), provide unique insights into normal and impaired myelopoiesis. The inherited neutropenias are heterogeneous in both clinical presentation and genetic associations, and their causative mechanisms are not well established. SCN, for example, is a genetically heterogeneous syndrome associated with mutations of ELANE, HAX1, GFI1, WAS, G6PC3, or CSF3R. The genetic diversity in SCN, along with congenital neutropenias associated with other genetically defined bone marrow failure syndromes (e.g., SDS), suggests that various pathways may be involved in their pathogenesis. Alternatively, all may lead to a final common pathway of enhanced apoptosis. The pursuit for a more complete understanding of the molecular mechanisms that drive inherited neutropenias remains at the forefront of pediatric translational and basic science investigation. Advances in our understanding of these disorders have greatly increased over the last 10 years concomitant with identification of their genetic lesions. Emerging themes include induction of the unfolded protein response (UPR), defective ribosome assembly, and p53-dependent apoptosis. Additionally, defects in metabolism, disruption of mitochondrial membrane potential, and mislocalization have been found. When perturbed, each of these lead to an intracellular stress that triggers apoptosis in the vulnerable granulocytic precursor.