title: Concise Review: Getting to the Core of Inherited Bone Marrow Failures.
abstract: Bone marrow failure syndromes (BMFS) are a group of disorders with complex pathophysiology characterized by a common phenotype of peripheral cytopenia and/or hypoplastic bone marrow. Understanding genetic factors contributing to the pathophysiology of BMFS has enabled the identification of causative genes and development of diagnostic tests. To date more than 40 mutations in genes involved in maintenance of genomic stability, DNA repair, ribosome and telomere biology have been identified. In addition, pathophysiological studies have provided insights into several biological pathways leading to the characterization of genotype/phenotype correlations as well as the development of diagnostic approaches and management strategies. Recent developments in bone marrow transplant techniques and the choice of conditioning regimens have helped improve transplant outcomes. However, current morbidity and mortality remain unacceptable underlining the need for further research in this area. Studies in mice have largely been unable to mimic disease phenotype in humans due to difficulties in fully replicating the human mutations and the differences between mouse and human cells with regard to telomere length regulation, processing of reactive oxygen species and lifespan. Recent advances in induced pluripotency have provided novel insights into disease pathogenesis and have generated excellent platforms for identifying signaling pathways and functional mapping of haplo-insufficient genes involved in large-scale chromosomal deletions-associated disorders. In this review, we have summarized the current state of knowledge in the field of BMFS with specific focus on modeling the inherited forms and how to best utilize these models for the development of targeted therapies. Stem Cells 2017;35:284-298.
authors.affiliation: Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA.|Hematology Department, Medical School, King Abdulaziz University, Jeddah, KSA.
authors.forename: Soheir
authors.initials: S
authors.lastname: Adam
authors.affiliation: Institute of Genetic Medicine, Newcastle University, United Kingdom.
authors.forename: Dario
authors.initials: D
authors.lastname: Melguizo Sanchis
authors.affiliation: Division of Human Genetics & Genome Research, National Research Center, Cairo, Egypt.
authors.forename: Ghada
authors.initials: G
authors.lastname: El-Kamah
authors.affiliation: Department of Hematology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom.
authors.forename: Sujith
authors.initials: S
authors.lastname: Samarasinghe
authors.affiliation: Princess Al Jawhara Al-Brahim Center of Excellence in Research of Hereditary Disorders, King Abdulaziz University, KSA.
authors.forename: Sameer
authors.initials: S
authors.lastname: Alharthi
authors.affiliation: Institute of Genetic Medicine, Newcastle University, United Kingdom.
authors.forename: Lyle
authors.initials: L
authors.lastname: Armstrong
authors.affiliation: Institute of Genetic Medicine, Newcastle University, United Kingdom.
authors.forename: Majlinda
authors.initials: M
authors.lastname: Lako
mesh_terms: D000741:Anemia, Aplastic / Q000473:pathology*; D000818:Animals; D001853:Bone Marrow / Q000473:pathology*; D001855:Bone Marrow Diseases / Q000473:pathology*; D000080983:Bone Marrow Failure Disorders; D004195:Disease Models, Animal; D006457:Hemoglobinuria, Paroxysmal / Q000473:pathology*; D006801:Humans; D008954:Models, Biological
keywords: Animal models; Human embryonic stem cells; Human induced pluripotent stem cells; Inherited bone marrow failures