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

MECOM-associated syndrome: a heterogeneous inherited bone marrow failure syndrome with amegakaryocytic thrombocytopenia

“…1 The underlying genes can be specific for hematopoietic cells, and hence, the symptoms are restricted to hematopoiesis, as in congenital amegakaryocytic thrombocytopenia (CAMT; Mendelian Inheritance in Man [MIM] #604498) caused by mutations in MPL. 2,3 However, a majority of IBMFSs are caused by defects in genes involved in common cellular pathways, such as transcriptional regulation, telomere maintenance, DNA repair, and ribosome function.…”

Bone marrow failure syndrome caused by homozygous frameshift mutation in the ERCC6L2 gene

“…1,2 Mutations in housekeeping genes, involved in DNA repair, the cell cycle, telomere maintenance and ribosome biogenesis, result in IBMFS. 3,4 Known syndromes, including Fanconi anemia, dyskeratosis congenita, Diamond-Blackfan anemia, and Schwachman-Diamond syndrome, are caused by mutations in genes in interconnecting pathways required for the maintenance of basic cellular function. 1,4 The genes involved in IBMFS are fundamental for the cell, which explains the increased risk for malignancies and congenital abnormalities associated with the syndromes.…”

“…Mutations in housekeeping genes, involved in DNA repair, the cell cycle, telomere maintenance and ribosome biogenesis, result in IBMFS . Known syndromes, including Fanconi anemia, dyskeratosis congenita, Diamond‐Blackfan anemia, and Schwachman‐Diamond syndrome, are caused by mutations in genes in interconnecting pathways required for the maintenance of basic cellular function .…”

Inherited and Acquired Bone Marrow Failure Syndromes: In the Era of Deep Gene Sequencing

“…Recent adoption of next generation gene sequencing led to the discovery of novel molecular markers in BMFS. More than 80 gene mutations in several biological pathways that are attributed to BMFS have been identified, including those involved in DNA repair, telomere biology, ribosome development, and genomic stability [8,9]. The key mutations associated with BMFS are summarized in Table 1.…”