title: 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.
authors.affiliation: 1] Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, Illinois [2] Division of Hematology, Oncology and Stem Cell Transplantation, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois [3] Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, Illinois.
authors.forename: Taly
authors.initials: T
authors.lastname: Glaubach
authors.affiliation: Department of Medicine, Division of Hematology-Oncology, Northwestern University Feinberg School of Medicine and Robert H. Lurie Comprehensive Cancer Center, Chicago, Illinois.
authors.forename: Alex C
authors.initials: AC
authors.lastname: Minella
authors.affiliation: 1] Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, Illinois [2] Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, Illinois [3] Department of Cell & Molecular Biology, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
authors.forename: Seth J
authors.initials: SJ
authors.lastname: Corey
mesh_terms: D000741:Anemia, Aplastic; D000818:Animals; D017209:Apoptosis; D001855:Bone Marrow Diseases; D000080983:Bone Marrow Failure Disorders; D020022:Genetic Predisposition to Disease; D006457:Hemoglobinuria, Paroxysmal / Q000151:congenital / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D009154:Mutation; D009503:Neutropenia / Q000151:congenital / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype; D012307:Risk Factors; D015398:Signal Transduction / Q000235:genetics; D013312:Stress, Physiological / Q000235:genetics