Recent insights into inherited bone marrow failure syndromes

Abstract

Purpose of the review Inherited bone marrow failure syndromes (IBMFS) are a diverse set of genetic disorders characterized by the inability of the bone marrow to produce sufficient circulating blood cells. The purpose of this review is to highlight novel findings in the last years and their impact into the understanding of IBMFS. Recent Findings Mutations in over 80 different genes have been associated with the development of bone marrow failure (BMF). The products of the genes mutated in IBMFS frequently participate in housekeeping pathways, which are important for cell growth and division rather than being specific for hematopoiesis. The common theme of these pathways, when disturbed, is the activation of p53, leading to cell cycle arrest, senescence, and cell death. With continued improvement in therapy for IBMFS, late complications, such as development of malignancies, are seen more frequently. This highlights the importance of understanding the affected pathways and their roles in cancer development. Summary The recent advancement of our understanding of IBMFS has come largely through the identification of the genetic lesions responsible for disease and the investigations of their pathways. Applied in clinical practice, these findings make it possible to unambiguously identify mutation carriers even before the development of BMF and exclude or confirm a suspected clinical diagnosis for many of the more common IBMFS. The further characterization of the pathways leading to IBMFS are likely to reveal novel targets for screening tests, prognostic biomarkers, and improved and specific therapeutics.

Global transcriptome analyses of human and murine terminal erythroid differentiation

“…[48][49][50] Another important use for these data sets is to develop a better mechanistic understanding of disordered erythropoiesis, with the ability to better understand stage-specific defects. This includes disorders such as the thalassemia syndromes, bone marrow failure syndromes and aplastic anemia [51][52][53][54][55][56] as well as acquired disorders such as the myelodysplasia syndromes, [57][58][59] particularly subtypes with disordered terminal erythroid differentiation. Numerous abnormalities have been identified in these disorders, including perturbed apoptosis, cytokine signaling, and regulation of cellular growth.…”

ICL-induced miR139-3p and miR199a-3p have opposite roles in hematopoietic cell expansion and leukemic transformation

“…1 Although the underlying causes of BMF syndromes are heterogeneous, they share the elevated risk to progress toward leukemia. 2 Ineffective repair of DNA damage is one of the major causes of BMF and leukemic transformation. 3 Fanconi anemia (FA) is the most frequently inherited cause of BMF.…”

Bone marrow failure unresponsive to bone marrow transplant is caused by mutations in thrombopoietin

“…Mutations in key intracellular pathways are responsible for the development of inherited BMF syndromes. 1,2 Replacement of the impaired hematopoietic system with a hematopoietic stem cell transplant constitutes the standard curative treatment approach for BMF disorders.…”