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Epigenetic Profiling of PTPN11 Mutant JMML Hematopoietic Stem and Progenitor Cells Reveals an Aberrant Histone Landscape
Abstract: Juvenile myelomonocytic leukemia (JMML) is a deadly pediatric leukemia driven by RAS pathway mutations, of which >35% are gain-of-function in PTPN11. Although DNA hypermethylation portends severe clinical phenotypes, the landscape of histone modifications and chromatin profiles in JMML patient cells have not been explored. Using global mass cytometry, Epigenetic Time of Flight (EpiTOF), we analyzed hematopoietic stem and progenitor cells (HSPCs) from five JMML patients with PTPN11 mutations. These data revealed statistically significant changes in histone methylation, phosphorylation, and acetylation marks that were unique to JMML HSPCs when compared with healthy controls. Consistent with these data, assay for transposase-accessible chromatin with sequencing (ATAC-seq) analysis revealed significant alterations in chromatin profiles at loci encoding post-translational modification enzymes, strongly suggesting their mis-regulated expression. Collectively, this study reveals histone modification pathways as an additional epigenetic abnormality in JMML patient HSPCs, thereby uncovering a new family of potential druggable targets for the treatment of JMML
Epigenetics and Pathology
This important book explores recent research by experts in the field pertaining to the role played by genetic factors in human pathology. A range of perspectives creates a well-rounded picture, including: host-pathogen interactions causal relationships between genes and the environment the effects of environmental chemicals on gene expression DNA methylation The book also covers the analysis and provides models for understanding the epigenetics-pathology connection. This book is designed for use by senior undergraduate and graduate students from several disciplines such as general, molecular, cellular biology, genetics, genomics, proteomics, and bioinformatics. It will also serve as a reference book for existing researchers and new investigators entering this rather unexplored field.
Advances In Pediatric Hematopoietic Cell Therapies And Transplantation
Dr Patrick Hanley, a Topic Editor for this collection, is a co-founder and serves on the board of directors of Mana Therapeutics, a private biotech company focused on cellular therapy for AML. All other Topic Editors declare no competing interests with regards to the Research Topic.
How to improve immune reconstitution in allogeneic hematopoietic stem cell transplantation?
Allogeneic haematopoietic stem cell transplantation (allo-HSCT) is widely used in the treatment of haematological malignancies as a form of immunotherapy acting through a graft-versus-leukemia (GvL) reaction. This curative allogeneic response can be associated with severe drawbacks, such as frequent and severe graft-versus-host disease (GvHD) and a long-lasting immunodeficiency, especially now with the development of innovative strategies such as umbilical cord blood transplantation or transplants from haplo-identical family donors (Haplo-HSCT). In the long-term follow-up of these patients, severe post-transplant infections, relapse or secondary malignancies may be directly related to persis...
NK Cell Subsets in Health and Disease: New Developments
Natural Killer (NK) cells were discovered ca 1975, as the first group of lymphoid cells that were neither T cells nor B cells. Since then, the dissection of the biology of NK cells has been growing exponentially with many seminal discoveries from the identification of MHC class I-specific inhibitory receptors to the discovery of receptor-ligand pairs involved in NK cell activation and to the manipulation of NK cells in cancer. In this research topic, we asked a group of thought leaders in NK cell biology to review recent advances in their origins and biology, and their roles in cancer, infection and inflammation. Together, these 25 articles provide a timely survey of NK cells as critical immunologic components of health and disease. They will hopefully prompt further dialogue and developments in basic and translational immunology.
Natural Killer Cells
To celebrate the 40th anniversary of the discovery of Natural Killer (NK) cells, this volume focuses on the recent advances in our understanding of NK cell development and differentiation and their acquisition of functional properties, as well as the latest models for NK-cell analysis in mice and applications in clinical medicine. NK cells have travelled a circuitous path from their initial description as ‘spontaneous killers’ (for some simply an experimental artifact) to being a bona fide subset of innate lymphoid cells with a complementary mode of action in immune defense and an important mediator of immune reactivity in health and disease. Together, these reviews provide a timely and concise picture of the evolution of NK cells as essential agents in immunity and as potent weapons against disease. This book offers an appealing and insightful resource for scientists and clinicians.
