The slippery slope of hematopoietic stem cell aging
• Changes in hematopoietic stem cells have been proposed to underlie hematopoietic aging• We previously generated iPS cells from individual and functionally defined aged HSCs• These iPS cells generated hematopoietic systems indistinguishable from those associating with young age• HSC aging a nd the potential for reversal are discussed (Source: Experimental Hematology)
Source: Experimental Hematology - September 21, 2017 Category: Hematology Authors: Martin Wahlestedt, David Bryder Source Type: research
Tessa Laurie Holyoake, (March 17, 1963 – August 30, 2017): Remembering a Life That Knew No Boundaries
Tessa Holyoake, MBChB, PhD, FRCP, FRCPath, FRSE, FMedSci, Professor of Experimental Haematology and Honorary Consultant in Haematology at the University of Glasgow and Founding Director of the Paul O'Gorman Leukemia Research Centre, died in the prime of her remarkable life, bravely and quietly of uncontrolled metastatic breast cancer on August 30, 2017. She was surrounded by a caring circle of family and friends and will be remembered with love and admiration by patients, colleagues, and a huge community of scientific followers around the world. (Source: Experimental Hematology)
Source: Experimental Hematology - September 20, 2017 Category: Hematology Authors: Connie J. Eaves Source Type: research
Persistent elevation of plasma thrombopoietin levels after treatment in severe aplastic anemia
• Longitudinal plasma TPO levels were detected in serial samples from AA patients.• Sustained high concentrations of TPO were observed in non-responders.• TPO levels declined but remained at high levels in complete responders over years. (Source: Experimental Hematology)
Source: Experimental Hematology - September 20, 2017 Category: Hematology Authors: Xin Zhao, Xingmin Feng, Zhijie Wu, Thomas Winkler, Ronan Desmond, Matthew Olnes, Bogdan Dumitriu, Danielle M. Townsley, Cynthia E. Dunbar, Neal S. Young Tags: Brief Communications Source Type: research
The GNASR201C mutation associated with clonal hematopoiesis supports transplantable hematopoietic stem cell activity
• GNASR201C mutation supports transplantable HSC activity.• GNASR201C mutation sustains lymphoid-differentiation potential of long-term HSCs.• GNASR201C mutations may contribute to CHIP, but not necessarily hematopoietic transformation. (Source: Experimental Hematology)
Source: Experimental Hematology - September 19, 2017 Category: Hematology Authors: Elizabeth L. Ostrander, Won Kyun Koh, Cates Mallaney, Ashley C. Kramer, W. Casey Wilson, Bo Zhang, Grant A. Challen Source Type: research
Identification of novel biomarkers for MLL translocated acute myeloid leukemia
• Human model AMLs has allowed the identification of new biomarkers for MLL-AML• qRT-PCR tests validate MLL-specific and pan-AML expression biomarkers• The novel biomarkers provide a more sensitive assay than current tests (Source: Experimental Hematology)
Source: Experimental Hematology - September 11, 2017 Category: Hematology Authors: Karine Lagac é, Fréderic Barabé, Josée Hebert, Sonia Cellot, Brian T. Wilhelm Tags: Brief Communications Source Type: research
Microrna-22 controls interferon alpha production and erythroid maturation in response to infectious stress in mice.
• MiR-22 knock-out mice have a blunted interferon response to viral infection.• MiR-22 exerts reciprocal effects on megakaryocyte and erythrocyte maintenance during infection.• MiR-22 is expressed in Stage II erythroid progenitors to regulate the pace of differentiation. (Source: Experimental Hematology)
Source: Experimental Hematology - September 11, 2017 Category: Hematology Authors: Claudine S. Kadmon, Cameron T. Landers, Haiyan S. Li, Stephanie S. Watowich, Antony Rodriguez, Katherine Y. King Source Type: research
Enhancement of mouse hematopoietic stem/progenitor cell function via transient gene delivery using integration-deficient lentiviral vectors.
• Integration-deficient vectors (IdLV) express genes transiently in dividing stem cells• Hematopoietic stem/progenitor (HSPC) cells can be programmed using IdLV• HOXB4 or Angptl3 expression from IdLV improves engraftment of transplanted HSPC• Short-term gene delivery avoids side effects asso ciated with constitutive expression• Disabled HIV has been modified so it cannot facilitate integration of thei delivered genome, causing short-term gene expression in dividing cells. Used in stem cells, this can alter their properties; for example, to improve the efficiency of bone marrow transpl antation. (So...
Source: Experimental Hematology - September 11, 2017 Category: Hematology Authors: Maria E. Alonso-Ferrero, Niek P. van Til, Kerol Bartolovic, M árcia F. Mata, Gerard Wagemaker, Dale Moulding, David A. Williams, Christine Kinnon, Simon N. Waddington, Michael D. Milsom, Steven J. Howe Source Type: research
Lenalidomide modulates gene expression in human ABC-DLBCL cells by regulating IKAROS interaction with an intronic control region of SPIB
• Mechanism of action of lenalidomide in ABC-DLBCL is not understood• SPIB is transcriptionally downregulated by lenalidomide• Lenalidomide-induced cell death in ABC-DLBCL involves SPIB downregulation• Lenalidomide-induced degradation of IKAROS is required for SPIB downregulation• IKAROS t ranscriptionally activates SPIB (Source: Experimental Hematology)
Source: Experimental Hematology - September 8, 2017 Category: Hematology Authors: Lauren A. Solomon, Carolina R. Batista, Rodney P. DeKoter Source Type: research
Thermal injury of the skin induces G-CSF-dependent attenuation of EPO-mediated STAT signaling and erythroid differentiation arrest in mice
The anemia of critical illness (ACI) develops in nearly all patients in the intensive care unit within 8 days of admission . ACI is a persistent anemia associated with an inappropriately low erythropoietin (EPO) response, poor marrow red cell production, and ongoing inflammation . Several inflammatory mediators have been proposed to suppress erythropoiesis through alterations of normal iron metabolism, EPO production or responsiveness, or erythroid progenitor differentiation and survival , but the mechanisms involved remain poorly understood. (Source: Experimental Hematology)
Source: Experimental Hematology - September 1, 2017 Category: Hematology Authors: John G. Noel, Benjamin J. Ramser, Jose A. Cancelas, Francis X. McCormack, Jason C. Gardner Source Type: research
Thermal injury of the skin induces G-CSF dependent attenuation of EPO-mediated STAT signaling and erythroid differentiation arrest in mice
• Erythroid mass is reduced following thermal injury despite constant EPO elevation.• Basal and EPO stimulated STAT signaling are impaired following thermal injury.• Impaired EPO signaling is associated reduced erythroid proliferation and viability.• G-CSF neutralization rescues medullary er ythropoiesis and erythroid STAT signaling. (Source: Experimental Hematology)
Source: Experimental Hematology - September 1, 2017 Category: Hematology Authors: John G. Noel, Benjamin J. Ramser, Jose A. Cancelas, Francis X. McCormack, Jason C. Gardner Source Type: research
Effects of in vivo deletion of GATA2 in bone marrow stromal cells
• GATA2 regulates genes involved in cell adhesion and chemotaxis in BM-MSCs.• Prx1-specific deletion of Gata2 in vivo compromised colony formation capacity.• CMP frequency was decreased by Gata2 deletion in the BM microenvironment. (Source: Experimental Hematology)
Source: Experimental Hematology - August 30, 2017 Category: Hematology Authors: Shin Hasegawa, Tohru Fujiwara, Yoko Okitsu, Hiroki Kato, Yuki Sato, Noriko Fukuhara, Yasushi Onishi, Ritsuko Shimizu, Masayuki Yamamoto, Hideo Harigae Source Type: research
Normal and neoplastic stem cell competition
Stem cell isolation and transplantation is the basis for regenerative medicine. We isolated mouse and then human hematopoietic stem cells (HSCs). Importantly, we demonstrated that transplantation of purified HSCs results in complete regeneration of the blood and immune systems without causing graft vs, host disease, and can induce permanent transplant tolerance of any organ or cell from the HSC donor. In a clinical trial in metastatic breast cancer patients HSC purification made autologous transplantation possible, without including cancerous cells in the graft. (Source: Experimental Hematology)
Source: Experimental Hematology - August 22, 2017 Category: Hematology Authors: Irving Weissman Source Type: research
Molecular and biological analysis of human hematopoietic stem cells at single-cell resolution
Elucidating the properties and processes regulating primitive hematopoietic cell behavior constitutes a clinically important but still elusive goal. A new challenge in addressing these questions has emerged from experiments in mice that have revealed multiple sources of intrinsically determined heterogeneity in the self renewal potential, lineage competence and proliferation state of these cells. In addition, it is has been shown that these key properties are not coordinately regulated when the cells are stimulated with different external cues. (Source: Experimental Hematology)
Source: Experimental Hematology - August 22, 2017 Category: Hematology Authors: Connie Eaves, D.J.H.F. Knapp, C.A. Hammond, A. Hui, M. van Loenhout, D. Pellacani, F. Wang, P.H. Miller, A. Lorzadeh, N. Aghaeepour, M. Moksa, M. Vaninsberghe, G.M. Rabu, P.A. Beer, R.K. Humphries, S. Bendall, G.P. Nolan, C. Hansen, M. Hirst Source Type: research
Humanized mice to study human hematopoietic stem cell function in vivo
Xenotransplantation models enable the in-depth analysis of human hematopoietic stem cell (HSC) function in vivo.We generated novel mouse models supporting stable HSC engraftment, which is a prerequisite for the continuous generation of all adult human hematopoietic cell types in mice. By introducing a loss-of-function Kit receptor into NOD/SCID Il2rg-/- (NSG) mice we generated NOD/SCID Il2rg-/- KitW41/W41 (NSGW41) mice that combine an impaired endogenous HSC compartment with immunodeficiency that efficiently support stable engraftment of human HSCs in the long-term without the need for any conditioning therapy. (Source: Ex...
Source: Experimental Hematology - August 22, 2017 Category: Hematology Authors: Claudia Waskow Source Type: research
Cellular hierarchy and molecular mechanisms underlying haematopoietic stem cell development
During embryonic development, adult haematopoietic stem cells (HSCs) emerge preferentially in the ventral domain of the aorta in the aorta –gonad–mesonephros (AGM) region. Using a combination of ex vivo and in vivo approaches, we found that stage-specific reciprocal dorso–ventral inductive interactions and lateral input from the urogenital ridges are required to drive HSC development in the aorta. These inductive interactions in the AGM region are mediated by the interplay between spatially polarized signalling pathways, which are integral parts of the regulatory system involved in the development of HSCs...
Source: Experimental Hematology - August 22, 2017 Category: Hematology Authors: Alexander Medvinsky, Stanislav Rybtsov, Alison McGarvey, Celine Souilhol, Antoniana Batsivari Source Type: research
Decoding hematopoietic stem cell emergence in mouse embryos at single-cell resolution
Hematopoietic stem cells (HSCs) are generated early from embryonic precursors, such as haemogenic endothelial cells and pre-HSCs located mainly in aorta-gonad-mesonephros (AGM) region. High level of CD201 expression is employed, together with other surface markers, to capture both CD45- and CD45+ individual pre-HSCs at 30% purity in E11 AGM, as rigorously validated by single-cell-initiated serial transplantation. Intriguingly, single pre-HSCs are capable of generating descendent HSCs with either myeloid-deficient ( γ) or lymphomyeloid balanced (β) potential. (Source: Experimental Hematology)
Source: Experimental Hematology - August 22, 2017 Category: Hematology Authors: Bing Liu Source Type: research
Quantitating native hematopoiesis
Recently, experimental tools have been developed for non-invasive labeling of hematopoietic stem cells (HSC), allowing the study of hematopoiesis at high resolution without experimental perturbation. This talk is based on data from mouse models developed in the Rodewald laboratory for in vivo fate mapping of HSC (using inducible Cre expressed from the Tie2 locus) and for endogenous, Cre-driven barcoding (using Polylox, a novel loxP-based barcode generator). I will address the following questions: (1) What are the cellular sources of definitive hematopoiesis in development and its maintenance during adulthood and aging, and...
Source: Experimental Hematology - August 22, 2017 Category: Hematology Authors: Thomas H öfer, Melania Barile, Katrin Busch, Thorsten Feyerabend, Weike Pei, Jens Rössler, Ann-Kathrin Schuon, Xi Wang, Hans-Reimer Rodewald Source Type: research
Mitochondrial regulation of hematopoietic stem cells
Hematopoietic stem cells (HSCs) are quiescent, can self renew, and generate all lineages of the hematopoietic system. Despite significant progress a coherent picture of how these mechanisms act in concert to regulate steady-state function and homeostatic responses of HSCs has not emerged yet.Furthermore, reliable renewal of HSCs in vitro has not been achieved, while there is overwhelming evidence that HSC self-renewal occurs in vivo. A particular gap is our understanding of the organellar cell biology of HSCs, which bridges transcriptional signatures to cellular functions. (Source: Experimental Hematology)
Source: Experimental Hematology - August 22, 2017 Category: Hematology Authors: Hans-Willem Snoeck Source Type: research
Regulation of stem and progenitor cell function by the bone vasculature
In addition to their conventional role as a conduit system for gases, nutrients, waste products or cells, blood vessels in the skeletal control multiple aspects of bone formation and provide niches for hematopoietic stem cells (HSCs) in bone marrow. Insight into the architecture and function of the vasculature in the skeletal system was previously limited by the heavily calcified and matrix-rich properties of bone. We have managed to overcome many of these limitations with the help of improved protocols for the processing, immunostaining and live imaging of bone (Kusumbe et al. (Source: Experimental Hematology)
Source: Experimental Hematology - August 22, 2017 Category: Hematology Authors: Ralf Adams Source Type: research
Inflammation-induced stress hematopoiesis
Infections are associated with extensive consumption of differentiated hematopoietic cells, representing a high risk for health. However, the mechanism coordinating the rapid and efficient regeneration of these differentiated cells during such stress conditions remains unclear. Recently, we have reported that the phenotypic hematopoietic stem cell (HSC) compartment contains stem-like megakaryocyte-committed progenitors (SL-MkPs), a cell population that shares many features with multipotent HSCs and serves as a lineage-restricted emergency pool for inflammatory insults. (Source: Experimental Hematology)
Source: Experimental Hematology - August 22, 2017 Category: Hematology Authors: Marieke Essers Source Type: research
Enhancer mechanisms governing developmental and regenerative hematopoietic programs
Establishment of the hematopoietic system requires the transcription factor GATA-2, and human GATA-2 mutations cause immunodeficiency, myelodysplastic syndrome, acute myeloid leukemia and vascular/lymphatic dysfunction. GATA-2-regulated enhancers differentially control Gata2 expression in hematopoietic stem/progenitor cells to ensure normal hematopoiesis. The enhancer +9.5 kb downstream of the transcription start site activates Gata2 transcription in endothelium and hematopoietic stem cells (HSCs), and its deletion in mice abrogates HSC generation. (Source: Experimental Hematology)
Source: Experimental Hematology - August 22, 2017 Category: Hematology Authors: Emery Bresnick, Kyle Hewitt, Charu Mehta, Kirby Johnson, Daniel Matson, Koichi Katsumura, Xin Gao, Skye McIver, Prithvia Devadas, Alexander Hebert, Joshua Coon, Jin-Soo Kim, Irene Ong, Erik Ranheim, Colin Dewey, Sunduz Keles, Robert Paulson Source Type: research
Global increase in replication fork speed during a p57KIP2-regulated erythroid cell fate switch
Cell cycle regulators are increasingly implicated in cell fate decisions such as the acquisition or loss of pluripotency and self-renewal potential. The cell cycle mechanisms that regulate these cell fate decisions are largely unknown. Here we studied an S phase- dependent cell fate switch, in which murine early erythroid progenitors transition in vivo from a self-renewal state into a phase of active erythroid gene transcription and concurrent maturational cell divisions. We found that progenitors are dependent on p57KIP2-mediated slowing of replication forks for self-renewal, a novel function for cyclin-dependent kinase (...
Source: Experimental Hematology - August 22, 2017 Category: Hematology Authors: Merav Socolovsky, Yung Hwang, Melinda Futran, Daniel Hidalgo Source Type: research
Elucidation of the mechanisms of hematopoietic reprogramming
Hematopoietic stem cell (HSC) transplantation is widely used to treat a variety of disorders. Despite advances in the use of umbilical cord blood and mobilized stem cells, donor material remains limited. This is due to insufficient numbers of stem cells in cord blood, poor mobilization, and the lack of ethnic diversity to provide sufficient genetically matched material. Despite intensive efforts there has been limited success in generating transplantable HSCs from pluripotent stem cells (PSCs). Clearly, alternative approaches are necessary. (Source: Experimental Hematology)
Source: Experimental Hematology - August 22, 2017 Category: Hematology Authors: Ihor Lemischka Source Type: research
Modeling human hematopoiesis in pluripotent stem cells
Hematopoietic stem cell (HSC) transplantation reconstitutes the blood cell compartment following myeloablative therapy or for patients with marrow aplasia. Because many patients do not have an optimal matched donor, the provision of HSCs from alternate sources, such as differentiated human pluripotent stem cells (hPSCs), is required. Despite considerable efforts, it has not been possible to efficiently generate repopulating HSCs from PSCs. Comparing the transcriptional profiles of hPSC-derived hematopoietic progenitors and repopulation-competent cord blood progenitors, we determined that failure to express HOXA genes in th...
Source: Experimental Hematology - August 22, 2017 Category: Hematology Authors: Andrew Elefanty, Elizabeth Ng, Freya Bruveris, Lisa Azzola, Belinda Phipson, Katerina Vlahos, Ana Rita Leuitoguinho, Vincenzo Calvanese, Katja Schenke-Layland, Alicia Oshlack, Hanna Mikkola, Edouard Stanley Source Type: research
From CRISPR-CAS9 drop-out screens to novel therapeutic approaches in acute myeloid leukaemia
Acute myeloid leukaemia (AML) is a devastating disease with a long-term survival of less than 30%. The study of its molecular pathogenesis through rational mechanistic studies has been at the center of efforts to identify novel therapeutic approaches against the disease, and these efforts have accelerated dramatically in recent years, propelled in part by advances in cancer genomics. Despite such progress cytarabine, developed more than 50 years ago, represents the last major addition to mainstream anti-AML therapy. (Source: Experimental Hematology)
Source: Experimental Hematology - August 22, 2017 Category: Hematology Authors: George Vassiliou Source Type: research
Towards identification and targeting of leukemic stem cells and (EPI)genetically distinct subclones using humanized niche xenograft mouse models
Over the past years it has become clear that multiple genetically distinct subclones can co-exist in patients that suffer from acute myeloid leukemia (AML). These subclones often carry similar founder mutations, but upon leukemic evolution different secondary mutations arise in distinct subclones. Tools to prospectively isolate viable subclones to functionally study them are currently lacking. We performed transcriptome and quantitative proteome analysis on large cohorts of primary AML CD34+ samples and healthy CD34+ controls. (Source: Experimental Hematology)
Source: Experimental Hematology - August 22, 2017 Category: Hematology Authors: Jan Jacob Schuringa Source Type: research
Emergence of definitive hematopoiesis in Myb-null mouse embryos
In the adult, the proto-oncogene Myb critically regulates both the maintenance of hematopoiesis and the differentiation of several hematopoietic lineages. Myb-null mouse embryos die beginning at embryonic day (E) 15.5 with severe anemia due to the absence of definitive erythropoiesis. These and other data have led to the concept that Myb-null embryos entirely lack hematopoietic stem cells (HSCs) and definitive hematopoiesis. During embryogenesis, the first definitive hematopoietic potential arises prior to HSCs as a wave of erythro-myeloid progenitors (EMP), which seed the liver and generate the first definitive erythrocyt...
Source: Experimental Hematology - August 22, 2017 Category: Hematology Authors: James Palis, Jenna Frame, Emanuele Azzoni, Anne Koniski, Jacquelyn Lillis, Marella de Bruijn, Kathleen McGrath Source Type: research
Resolving the fetal to adult switch in B lymphopoiesis at the single cell level
In mice and men, a developmental switch takes place in immune cell output early in life. This is likely designed to accommodate the unique demands of tolerance both in utero and during neonatal exposure to environmental antigens, while providing protection against common pathogens. In the murine B cell lineage, the output of B-1 cells is predominant in utero and diminishes within weeks after birth in favor of conventional follicular B-2 cells. B-1 cells constitute a non-redundant aspect of the immune repertoire that controls infection and inflammation through T-independent secretion of natural antibodies and IL-10. (Source...
Source: Experimental Hematology - August 22, 2017 Category: Hematology Authors: Joan Yuan, Trine Kristiansen, Stijn Vanhee, Elin Jaensson-Gyllenb äck, Alya Zriwil, Alexander Doyle, Ewa Sitnicka Quinn, Stefan Lang, Shamit Soneji, David Bryder Source Type: research
MLL family histone methyltransferases in hematopoiesis and leukemia
Six histone H3, lysine 4 (H3K4) methyltransferases are co-expressed in many tissues, maintaining the H3K4me1/me2/ me3 enrichment found at enhancers and promoters, modifications that generally enhance gene expression. These enzymes include MLL1-MLL4 (Kmt2a-Kmt2d) and SETD1a/SETD1b (Kmt2e/Kmt2f). Several of these enzymes have been implicated in normal hematopoiesis and leukemia, but how they target and influence specific genes in specific cell types is largely unknown. The MLL1 gene undergoes many distinct chromosomal rearrangements to yield poor-prognosis leukemia. (Source: Experimental Hematology)
Source: Experimental Hematology - August 22, 2017 Category: Hematology Authors: Patricia Ernst, Yufei Chen Source Type: research
Post-transcriptional and metabolic regulation of erythropoiesis
Cellular differentiation requires highly coordinated gene expression through transcriptional and post-transcriptional mechanisms. Advances in high-throughput sequencing enabled genome-scale quantification of mRNA for gene expression, yet the extent to which changes in mRNA are translated to protein remains unclear. Here we measured genome-wide protein and mRNA expression in human primary fetal liver and adult bone marrow-derived CD34+ hematopoietic stem/progenitor cells (HSPCs) and differentiated erythroid precursors (proerythroblasts or ProEs) by mass-spectrometry-based quantitative proteomics and RNA-seq analysis, respec...
Source: Experimental Hematology - August 22, 2017 Category: Hematology Authors: Jian Xu Source Type: research
Roundabout ways to lineage commitment
The lineage potential, heterogeneity, and relationships of hematopoietic stem and progenitor cells (HSPCs) are currently unclear. To gain new insights into these questions, we performed quantitative analyses of mature cell production by transplanted HSPCs. Assessment of the absolute numbers of mature cell types produced by each progenitor cell revealed a striking erythroid bias of all myeloid-competent progenitors assessed, accompanied by strong platelet production that far exceeded generation of myelomonocytic, B and T cells. (Source: Experimental Hematology)
Source: Experimental Hematology - August 22, 2017 Category: Hematology Authors: Camilla Forsberg Source Type: research
Genetic variation underlies epigenomic variation and the consequences of DNMT3A mutation in hematopoietic stem cells
Accumulation of somatic mutations in genes including the DNA methyltransferase DNMT3A predisposes many, but not all, individuals to development of clonal hematopoiesis and acute myeloid leukemia (AML). We hypothesize that individual genetic variation underlies distinct epigenomic patterning, and that this variation alters susceptibility to the pathogenic consequences of DNMT3A mutations in hematopoietic stem cells (HSCs). Through a collaborative effort to assess epigenome variation in a genetically diverse model system, we performed an in-depth chromatin analysis of liver cells isolated from 8 classical and wild-derived in...
Source: Experimental Hematology - August 22, 2017 Category: Hematology Authors: Jennifer Trowbridge, Rebecca Bell, Catrina Spruce, Anna Tyler, Robyn Ball, Vivek Philip, Dan Gatti, Narayanan Raghupathy, Romy Kurasawe, Kira Young, Mary Ann Handel, Michael Stitzel, Gary Churchill, Kenneth Paigen, Petko Petkov, Gregory Carter Source Type: research
Mitochondria in the regulation of hematopoietic stem cells
Hematopoietic stem cells (HSCs) like most, if not all, adult stem cells are primarily quiescent but have the potential to become highly active when needed. HSCs accumulate low levels of reactive oxygen species (ROS) despite containing a significant number of mitochondria suggesting that mitochondria are relatively inactive in quiescent HSC. However, HSC cycling – and exit of quiescence state – involves a switch to mitochondrial oxidative phosphorylation from glycolysis. While HSC differentiation requires mitochondrial metabolism, the role of mitochondria in the maintenance of HSC quiescence is less clear. (Sour...
Source: Experimental Hematology - August 22, 2017 Category: Hematology Authors: Saghi Ghaffari Source Type: research
Epigenetic stress response and stem cell aging
Adult tissue stem cells contribute to the lifelong maintenance of 0rgan homeostasis and regeneration. However, the functionality of stem cells declines during aging and there is emerging evidence for the clonal dominance of mutant stem cells. Both processes contribute to the evolution of aging associated dysfunctions and diseases but molecular mechanisms that impair the function of stem cells during aging remain incompletely understood. Our recent work revealed that alterations in epigenetic stress responses lead to an aberrant activation of developmental pathways that impair the self renewal and regenerative capacity of m...
Source: Experimental Hematology - August 22, 2017 Category: Hematology Authors: Lenhard Rudolph, Zhyjang Chen Source Type: research
Clinical outcomes of lentiviral gene therapy for the beta-hemogolobinpathies
See online program addendum. (Source: Experimental Hematology)
Source: Experimental Hematology - August 22, 2017 Category: Hematology Authors: Philippe Leboulch Source Type: research
Synthetic biology in cellular immunotherapy
The transfer of tumor-targeting T cells to patients is a promising approach for cancer immunotherapy. Despite these encouraging results, many challenges remain to be addressed before T cell therapy can be widely adopted. Here I will describe our efforts in using synthetic biology to develop genetic circuits and switches for modulating T cell activation. These genetic tools will provide tools for managing the toxicity associated with T cell therapy. (Source: Experimental Hematology)
Source: Experimental Hematology - August 22, 2017 Category: Hematology Authors: Wilson Wong Source Type: research
Intravital microscopy reveals dynamic and selective microenvironment remodeling by diverse types of acute leukemia
Hematopoietic stem cell (HSC) function requires bone marrow niches, which have been proposed to be co-opted by leukemia cells to support their propagation. Using both an experimental model and human bone marrow samples of T-cell acute lymphoblastic leukemia (T-ALL), we documented dramatic remodeling of the osteoblastic lineage, while T-ALL cells appeared to be microenvironment agnostic throughout disease progression. More recently, we have analysed an acute myeloid leukemia (AML) experimental model, in which we uncovered hierarchical vascular remodeling with AML progression. (Source: Experimental Hematology)
Source: Experimental Hematology - August 22, 2017 Category: Hematology Authors: Cristina Lo Celso Source Type: research
Toward high-throughput functional epigenomics using CRISPR single-cell sequencing
International consortia have mapped the human epigenome in hundreds of cells types. These maps are being refined by ongoing single-cell sequencing projects, which will eventually give rise to a comprehensive catalog of all cells in the human body. However, we are lagging behind with our ability to assign biological functions to the observed gene regulatory patterns. CRISPR-based genetic screens have the potential to accelerate functional studies, but current methods have inherent limitations. Widely used pooled screens are restricted to simple readouts including cell proliferation and sortable marker proteins. (Source: Exp...
Source: Experimental Hematology - August 22, 2017 Category: Hematology Authors: Christoph Bock Source Type: research
Pioneer factors in T cells
Hematopoietic progenitors seed the thymus to initiate the T cell differentiation program. This pathway is orchestrated by a cadre of transcription factors deploying a T cell-restricted gene expression program initially buried within inaccessible chromatin. Despite the breath of knowledge on essential transcription factors in T cell development, the proteins responsible for the de novo gain of chromatin accessibility, also known as ‘pioneer’ factors, remain unknown. Here, we report the critical role of a T cell specific transcription factor in creating de novo chromatin accessibility. (Source: Experimental Hematology)
Source: Experimental Hematology - August 22, 2017 Category: Hematology Authors: Golnaz Vahedi Source Type: research
Role of mutations in epigenetic regulators in the pathogenesis of AML
Clinical, cytogenetic, and gene-based studies have been used to inform biology and improve prognostication for patients with acute myeloid leukemia (AML). Candidate gene and whole genome studies have identified recurrent somatic mutations in AML patients including TET2, ASXL1, DNMT3A, and cohesin complex mutations. We and others have found that TET2/IDH mutations leads to loss of DNA hydroxymethylation and a hypermethylation phenotype in leukemia patients. In addition, in vitro and in vivo studies show that TET2 loss or neomorphic IDH1/2 mutations leads to impaired hematopoietic differentiation, increased stem cell self-re...
Source: Experimental Hematology - August 22, 2017 Category: Hematology Authors: Ross Levine Source Type: research
First-in-class, oral mutant IDH2 inhibitor reverses differentiation block in acute myeloid leukaemia to produce clinically meaningful responses
Acute Myeloid Leukaemia (AML) is the most common aggressive human leukaemia. ∼15% of AML cases have acquired point mutations in the gene Isocitrate Dehydrogenase 2. Mutant IDH2 (mIDH2) protein has neomorphic gain-of-function enzyme activity resulting in R-2-hydroxyglutarate (2-HG) accumulation. 2-HG competitively inhibits the TET family of 5-methylcytosine (5mC) hydroxylas es and the Jumonji-C domain histone demethylases(. This leads to DNA hypermethylation, increased repressive histone methylation (6) and a differentiation block. (Source: Experimental Hematology)
Source: Experimental Hematology - August 22, 2017 Category: Hematology Authors: Paresh Vyas Source Type: research
Transcription factor induced reprogramming of B cells
The mechanism by which cells decide what to become is of fundamental importance for basic biology and human disease, yet it is still poorly understood. Using committed B cell precursors as a model our laboratory studies how these cells can be transdifferentiated into macrophages on the one hand or reprogrammed into induced pluripotent stem cells (iPSCs) on the other. Both processes involve overexpression of the transcription factor C/EBPa, with transdifferentiation into macrophages requiring sustained expression levels of the factor and highly efficiency reprogramming into iPSCs requiring a pulse of C/EBPa followed by the ...
Source: Experimental Hematology - August 22, 2017 Category: Hematology Authors: Thomas Graf, Ralph Stadhouders, Jose Sardina, Gregoire Stik, Johanna Goldmann, Mirko Francesconi, Ben Lehner, Bruno Di Stefano, Samuel Collombet Source Type: research
New strategies for targeting leukemia stem cells
In this presentation, we will document our new strategies for the identification and ex vivo growth of primary leukemia stem cells. We will also show how we can exploit these newly developed methodologies to screen for compounds that specifically synergize to destroy leukemia stem cells. This includes cellular response to compounds and correlations of such responses to genetic anomalies found in each leukemia specimen. Redundancy of synthetic lethality between specimens appears to be predictable by companion tests which are being developed by our group. (Source: Experimental Hematology)
Source: Experimental Hematology - August 22, 2017 Category: Hematology Authors: Guy Sauvageau Source Type: research
Regulation of vertebrate hematopoiesis
Hematopoietic stem cells (HSCs) give rise to each of the blood lineages found in the adult vertebrate for the lifetime of the host. The gene programs regulating HSC development and homeostasis are highly evolutionarily conserved and initiate during embryonic stages from analogous developmental niches. Critically, intrinsic or extrinsic deregulation of hematopoiesis can result in hematologic disorders and/or malignancies, including leukemia. Using an unbiased chemical screening approaches and targeted genetic modulation, we have identified several key regulatory pathways that impact the specification and/or expansion of Run...
Source: Experimental Hematology - August 22, 2017 Category: Hematology Authors: Trista North Source Type: research
Barcoding of human haematopoietic stem and progenitor cells by whole genome sequencing reveals clonal dynamics of haematopoiesis
The number of hematopoietic stem cells (HSCs) in humans and the dynamics of how these contribute to blood over time are critical to our understanding of normal hematopoiesis and its subversion in disease. While molecular barcoding or lineage tracing approaches have been applied to assess the output of single HSCs in animal models, similar approaches have not been possible in unperturbed human hematopoiesis. To address this, we investigated hematopoietic dynamics by using somatic mutations as barcodes. (Source: Experimental Hematology)
Source: Experimental Hematology - August 22, 2017 Category: Hematology Authors: Henry Lee-Six, Nina Friesgaard-Oebro, Mairi Shepherd, Sebastian Grossmann, Kevin Dawson, Miriam Belmonte, Robert Osborne, Inigo Martincorena, Carlos Gonzalez Arias, Jacob Grinfeld, Elisa Laurenti, Brian Huntly, Michael Stratton, Tony Green, David Kent, Pe Source Type: research
New delineation of human CD34+ stem/progenitor cell hierarchical organization
Human CD34+ stem/progenitor cell compartment has been recently re-defined and within the Lin-CD34+CD38-CD45RA- fraction it is possible to separate 4 sub-populations based on CD90 and CD49f expressions (simply refer as CD90+/-CD49f+/-). CD90+CD49f+ and CD90-CD49f- cells have been proved to be HSCs and MPPs (multipotent progenitors) respectively. However, it is unclear what is the relationship between the remaining two sub-populations (CD90+CD49f- and CD90-CD49f+) with the CD90+CD49f+ HSC and CD90-CD49f- MPP fractions. (Source: Experimental Hematology)
Source: Experimental Hematology - August 22, 2017 Category: Hematology Authors: Fernando Anjos-Afonso, Florian Buettner, Dominique Bonnet Source Type: research
MLLT3 sustains human HSC self-renewal and engraftment
The use of hematopoietic stem cells (HSC) for treating hematopoietic malignancies and genetic disorders is limited by availability of HLA-matched donors. If HSC could be expanded in culture or derived from pluripotent stem cells (PSCs), the number of patients and the spectrum of treatable diseases would greatly increase. To uncover the genetic network that promotes HSC self-renewal, we identified genes whose expression is enriched in self-renewing human hematopoietic stem and progenitor cells (HSPC) in fetal liver (FL), and that are down-regulated in cultured HSPC. (Source: Experimental Hematology)
Source: Experimental Hematology - August 22, 2017 Category: Hematology Authors: Vincenzo Calvanese, Andrew T. Nguyen, Timothy Bolan, Zoran Galic, Hanna Mikkola Source Type: research
Single cells undergoing cell fate change during endothelial-to-hematopoietic cell transition show pulsatile Gata2 expression
Underpinning cell behavior during development and differentiation, are fundamental dynamic expression changes that drive cell fate processes away from a pre-existing equilibrium. The Gata2 transcription factor is an important regulator of blood cell differentiation and development, and is pivotal to hematopoietic stem cell generation (HSC). Within a short window of developmental time HSCs originate from a natural differentiation of hemogenic endothelial cells through a process called endothelial to hematopoietic transition (EHT). (Source: Experimental Hematology)
Source: Experimental Hematology - August 22, 2017 Category: Hematology Authors: Elaine Dzierzak, Christina Eich, Jochen Arlt, Chris Vink, Wiggert van Cappellen Source Type: research