Increasing complexity of molecular landscapes in human hematopoietic stem and progenitor cells during development and aging

The past five decades have seen significant progress in our understanding of human hematopoiesis. This has in part been due to the unprecedented development of advanced technologies, which have allowed the identification and characterization of rare subsets of human hematopoietic stem and progenitor cells and their lineage trajectories from embryonic through to adult life. Additionally, surrogate in vitro and in vivo models, although not fully recapitulating human hematopoiesis, have spurred on these scientific advances. These approaches have heightened our knowledge of hematological disorders and diseases and have led to their improved diagnosis and therapies. Here, we review human hematopoiesis at each end of the age spectrum, during embryonic and fetal development and on aging, providing exemplars of recent progress in deciphering the increasingly complex cellular and molecular hematopoietic landscapes in health and disease. This review concludes by highlighting links between chronic inflammation and metabolic and epigenetic changes associated with aging and in the development of clonal hematopoiesis

Cell-type-specific transcriptional regulation of PIGM underpins the divergent hematologic phenotype in inherited GPl deficiency.

A rare point mutation in the core promoter -270GC-rich box of PIGM, a housekeeping gene, disrupts binding of the generic transcription factor (TF) Sp1 and causes inherited glycosylphosphatidylinositol (GPI) deficiency (IGD). We show that whereas PIGM messenger RNA levels and surface GPI expression in IGD B cells are low, GPI expression is near normal in IGD erythroid cells. This divergent phenotype results from differential promoter chromatin accessibility and binding of Sp1. Specifically, whereas PIGM transcription in B cells is dependent on Sp1 binding to the -270GC-rich box and is associated with lower promoter accessibility, in erythroid cells, Sp1 activates PIGM transcription by binding upstream of (but not to) the -270GC-rich box. These findings explain intact PIGM transcription in IGD erythroid cells and the lack of clinically significant intravascular hemolysis in patients with IGD. Furthermore, they provide novel insights into tissue-specific transcriptional control of a housekeeping gene by a generic TF

Cell-type-specific transcriptional regulation of PIGM underpins the divergent hematologic phenotype in inherited GPl deficiency.

A rare point mutation in the core promoter -270GC-rich box of PIGM, a housekeeping gene, disrupts binding of the generic transcription factor (TF) Sp1 and causes inherited glycosylphosphatidylinositol (GPI) deficiency (IGD). We show that whereas PIGM messenger RNA levels and surface GPI expression in IGD B cells are low, GPI expression is near normal in IGD erythroid cells. This divergent phenotype results from differential promoter chromatin accessibility and binding of Sp1. Specifically, whereas PIGM transcription in B cells is dependent on Sp1 binding to the -270GC-rich box and is associated with lower promoter accessibility, in erythroid cells, Sp1 activates PIGM transcription by binding upstream of (but not to) the -270GC-rich box. These findings explain intact PIGM transcription in IGD erythroid cells and the lack of clinically significant intravascular hemolysis in patients with IGD. Furthermore, they provide novel insights into tissue-specific transcriptional control of a housekeeping gene by a generic TF

Guidelines for the investigation and management of Transient Leukaemia of Down Syndrome

Methodology This guideline was compiled according to the British Society for Haematology (BSH) process at (http://www.bcshguidelines.com). The Grading of Recommendations Assessment, Development and Evaluation (GRADE) nomenclature was used to evaluate levels of evidence and to assess the strength of recommendations. The GRADE criteria can be found at http://www.gradeworkinggroup.org. Literature review details Ovid MEDLINE and Ovid EMBASE were searched systematically for publications in English from 1980 to the end of 2015 using the key words Transient Abnormal Myelopoiesis, Transient Myeloproliferative Disorder, Transient Leukaemia, and Down Syndrome. Specific searches relating to fetal disease and hepatic parameters were also performed. References from relevant publications were also searched. Working group membership The guideline group was selected to be representative of UK‐based medical experts with invited representatives from the British Association of Perinatal Medicine and the Royal College of Paediatrics and Child Health. Review Review of the manuscript was performed by the BSH Guidelines General Haematology Task Force, the BSH Guidelines Committee and the General Haematology sounding board of BSH. It was also placed on the members section of the BSH website for comment. Further comments were invited from a sounding board of the Childhood Leukaemia Clinicians'27 Network, the Childhood Cancer and Leukaemia Group (CCLG), the Royal College of Paediatrics and Child Health, the British Association of Perinatal Medicine (BAPM) and patient representatives identified through the Down Syndrome Association; these organisations do not necessarily approve or endorse the contents. The objective of this guideline is to provide healthcare professionals with guidance on the investigation and management of patients with Transient Leukaemia of Down Syndrome (TL‐DS). Individual patient circumstances may dictate an alternative approach. This is the first BSH guideline on this topic and is in date at time of publication. Any updates will be posted on the BSH Guidelines website (http://www.bcshguidelines.com).</p