Methylation age as a correlate for allele burden, disease status and clinical response in myeloproliferative neoplasm patients treated with Vorinostat
The myeloproliferative neoplasms (MPNs) are a group of clonal hematological disorders, where there is a change from the polyclonal hematopoiesis seen in health, to an abnormal monoclonal proliferation of blood cells. Polycythemia vera (PV) and essential thrombocythemia (ET) are characterized respectively by the excess production of red blood cells and platelets. Identification of the JAK2 V617F driver mutation, in 95% of PV cases and 50% of ET cases, causing constitutive activation of the JAK/STAT pathway has revolutionized our understanding of the pathogenesis of these conditions.(1) In JAK2 V617F negative cases driver mu...
Source: Experimental Hematology - September 26, 2019 Category: Hematology Authors: S. McPherson, G. Greenfield, C. Andersen, J. Grinfeld, H. Hasselbalch, J. Nangalia, K.I. Mills, MF. McMullin Source Type: research

Application of blood and immunodeficiency gene detection in the diagnosis of hemophagocytic lymphohistiocytosis patients
Hemophagocytic lymphohistiocytosis (HLH) is caused by excessive activation of lymphocytes and histiocytes, secretion of a large number of cytokines, which eventually leads to fatal inflammatory damage, characterized by damages to multiple organs, rapid disease progression and high mortality. HLH can be divided into primary and secondary HLH according to etiology. Primary HLH includes familial HLH (FLH) and immunodeficiency-related HLH. The former can be classified into five types: FHL1 –FHL5. The latter include Chediak–Higashi syndrome 1, Glicelli syndrome II, Hermansky–Pudlak syndrome II, X-linked lympho...
Source: Experimental Hematology - September 25, 2019 Category: Hematology Authors: Wenyuan Mo, Wei Wei, Yan Sun, Yanhong Yang, Zebing Guan, Mingjie Li, Ping Zhu, Zuohua Chi Tags: Regular submission Source Type: research

Rats offer a superior model of human stress erythropoiesis
Mouse models are the most commonly used laboratory animal models to study human erythropoiesis. The identification of several unique cell surface markers on the developing mouse erythroid precursors enables step-by-step cellular and molecular investigations of terminal erythropoiesis from erythroid colony forming units (CFU-E) to mature red blood cells in vitro. Among these markers, CD71 and Ter119 were first used almost two decades ago to characterize terminal erythropoiesis in mouse bone marrow and spleen [1,2], and later in the fetal liver [3]. (Source: Experimental Hematology)
Source: Experimental Hematology - September 25, 2019 Category: Hematology Authors: Jingxin Zhang, Yijie Liu, Xu Han, Yang Mei, Jing Yang, Zheng J. Zhang, Xinyan Lu, Peng Ji Source Type: research

Modest and non-essential roles of the endocannabinoid system in immature hematopoiesis of mice
Hematopoiesis, i.e. the continuous, life-long process of generating short-lived mature blood cells, originates from hematopoietic stem and progenitor cells (HSPCs) [1], the proliferation of which is tightly controlled. The hematopoietic organ is physically located in the bone marrow (BM) where HSPCs interact in an intricate fashion with their environment, the niche [2]. Under the influence of the latter, HSPCs give rise to increasingly more differentiated precursors and mature blood cells which are ultimately released into the peripheral blood [3]. (Source: Experimental Hematology)
Source: Experimental Hematology - September 25, 2019 Category: Hematology Authors: Eva Danner, Frauke Hoffmann, Seo-Youn Lee, Fabian Cordes, Sabine Orban, Katrin Dauber, Doreen Chudziak, Gabriele Spohn, Eliza Wiercinska, Benjamin Tast, Darja Karpova, Halvard Bonig Source Type: research

Application of detection of mutations in blood and immunodeficiency genes in the diagnosis of HLH patients
HLH is caused by excessive activation of lymphocytes and histiocytes, secretion of a large number of cytokines, which eventually leads to fatal inflammatory damage, characterized by damages to multiple organs, rapid disease progression and high mortality. HLH can be divided into primary and secondary HLH according to etiology. Primary HLH includes familial HLH (FLH) and immunodeficiency-related HLH. The former can be classified into five types: FHL1-FHL5. The latter includes Chediak-Higashi syndrome 1, Glicelli syndrome II, Hermansky-Pudlak syndrome II, X-linked lymphoid tissue proliferation syndrome 1 and X-linked lymphop...
Source: Experimental Hematology - September 25, 2019 Category: Hematology Authors: Wenyuan Mo, Wei Wei, Yan Sun, Yanhong Yang, Zebing Guan, Mingjie Li, Ping Zhu, Zuohua Chi Source Type: research

Immature platelet fraction as a useful marker in the etiological determination of thrombocytopenia
Thrombocytopenia is a finding that is common to a number of underlying conditions [1 –4]. Accurate identification of etiology is critical to appropriate management of these patients. Thrombocytopenia is defined as a platelet count (PLT) below the 2.5th percentile of a normal platelet distribution, with a concentration (Source: Experimental Hematology)
Source: Experimental Hematology - September 24, 2019 Category: Hematology Authors: Imtiaz Ali, Ciaren Graham, Nina C. Dempsey-Hibbert Tags: Regular submission Source Type: research

Immature Platelet Fraction as a useful marker in the aetiological determination of Thrombocytopenia
Thrombocytopenia is a finding common to a number of underlying conditions [1-4]. Accurate identification of aetiology is critical to appropriate management of these patients. Thrombocytopenia is defined as a platelet count (PLT) below the 2.5th percentile of a normal platelet distribution, with a concentration (Source: Experimental Hematology)
Source: Experimental Hematology - September 24, 2019 Category: Hematology Authors: Imtiaz Ali, Ciaren Graham, Nina C. Dempsey-Hibbert Source Type: research

Glycolytic enzyme hexokinase II is a putative therapeutic target in B cell malignant lymphoma
Malignant lymphoma cells tend to use glycolysis to produce ATP even when a substantial oxygen supply is available, a process known as aerobic glycolysis, as illustrated by the high uptake of FDG-glucose. Hexokinases (HXKs) are a family of enzymes that catalyze the first step in glucose metabolism. There are four major HXKs, HXK I, II, III and IV. Among these members, HXKII uniquely shows abnormal elevation in numerous types of cancer and is thought to play crucial roles in aerobic glycolysis in cancer cells. (Source: Experimental Hematology)
Source: Experimental Hematology - September 24, 2019 Category: Hematology Authors: Kei Nakajima, Ichiro Kawashima, Megumi Koshiisi, Takuma Kumagai, Megumi Suzuki, Jun Suzuki, Toru Mitsumori, Keita Kirito Source Type: research

Machine learning predicts putative haematopoietic stem cells within large single-cell transcriptomics datasets
It has been over 60 years since experiments first proved the existence of bone marrow cells capable of producing the whole blood system. In the following decades, multipotent haematopoietic stem cells (HSCs) have been the subject of many studies aimed at revealing the mechanisms controlling their function [1]. Strategies to isolate blood cells were developed following the invention of techniques to sort cells based on their expression of specific proteins. By isolating and transplanting different fractions of bone marrow, sorting strategies could be refined to enrich for populations passing the gold-standard stem cell assa...
Source: Experimental Hematology - September 9, 2019 Category: Hematology Authors: Fiona K. Hamey, Berthold G öttgens Source Type: research

Daily light and darkness onset and circadian rhythms metabolically synchronize hematopoietic stem cell differentiation and maintenance: The role of bone marrow norepinephrine, TNF and melatonin cycles
Hematopoietic stem and progenitor cells (HSPC) dynamically replenish the blood with new mature blood and immune cells with a finite lifespan, while maintaining and renewing the undifferentiated HSPC bone marrow (BM) reservoir. Long-term repopulating HSC (LT-HSC) are identified and characterized in preclinical experimental transplantation assays, based on their functional ability to home and to durably repopulate the bone marrow (BM) and blood with high levels of both myeloid and lymphoid cells. Short-term repopulating HSPC are metabolically active with high levels of reactive oxygen species (ROShigh), giving rise to myeloi...
Source: Experimental Hematology - September 5, 2019 Category: Hematology Authors: Karin Golan, Orit Kollet, Regina P. Markus, Tsvee Lapidot Tags: Review Source Type: research

BCR-ABL1 tyrosine kinase inhibitor K0706 exhibits preclinical activity in Philadelphia chromosome-positive leukemia
Patients with chronic-phase CML (CP-CML) are effectively managed with BCR-ABL1 tyrosine kinase inhibitors (TKIs), and their survival approaches that of age-matched controls [1]. K0706 was designed as a BCR-ABL1 TKI to provide an option for patients experiencing resistance or intolerance to the first-line TKIs imatinib, nilotinib, dasatinib, and bosutinib [2,3]. Structural elements that overlap with dasatinib and ponatinib are noted (Figure 1A). (Source: Experimental Hematology)
Source: Experimental Hematology - September 4, 2019 Category: Hematology Authors: Orlando Antelope, Nadeem Vellore, Anthony D. Pomicter, Ami B. Patel, Alexandria van Scoyk, Phillip M. Clair, Michael Deininger, Thomas O'Hare Tags: Fast Track Submission Source Type: research

BCR-ABL1 tyrosine kinase inhibitor K0706 exhibits pre-clinical activity in Philadelphia chromosome-positive leukemia
Patients with chronic phase CML (CP-CML) are effectively managed with BCR-ABL1 tyrosine kinase inhibitors (TKIs) and their survival approaches that of age-matched controls [1]. K0706 was designed as a BCR-ABL1 TKI to provide an option for patients experiencing resistance or intolerance to the first-line TKIs imatinib, nilotinib, dasatinib, and bosutinib [2,3]. Structural elements that overlap with dasatinib and ponatinib are noted (Figure 1A). (Source: Experimental Hematology)
Source: Experimental Hematology - September 4, 2019 Category: Hematology Authors: Orlando Antelope, Nadeem Vellore, Anthony D. Pomicter, Ami B. Patel, Alexandria van Scoyk, Phillip M. Clair, Michael Deininger, Thomas O'Hare Tags: Brief Communication Source Type: research

Increased platelet function during frailty
Increase in life expectancy worldwide have generated a growth in the populations of older adults in almost every country throughout the world [1,2]. A greater state of physical and mental vulnerability can occur during aging, which is known as frailty. This is defined as an increase in susceptibility to adverse outcomes, including disability, dependency, falls, need for long-term care, and mortality [3]. This is also characterized by a multisystem deregulation that can be clinically identified by weight loss, increase in weakness, poor endurance and energy, slowness and low physical activity [4]. (Source: Experimental Hematology)
Source: Experimental Hematology - August 30, 2019 Category: Hematology Authors: B. Hern ández, E. Fuentes, I. Palomo, M. Alarcón Source Type: research

Biological implications of clonal hematopoiesis
Blood formation, or hematopoiesis, is essential for human health.1 The blood and immune systems are responsible to providing the body with oxygen and nutrients, supporting wound healing, and fighting pathogens. These functions are carried out by the various cell types that constitute the hematopoietic system: red blood cells; platelets; innate immune cells (neutrophils, monocytes, etc.); and adaptive immune cells (T cells, B cells). To maintain hematopoietic system homeostasis, new blood cells must be constantly produced. (Source: Experimental Hematology)
Source: Experimental Hematology - August 28, 2019 Category: Hematology Authors: Tiago C. Luis, Adam C. Wilkinson, Isabel Beerman, Siddhartha Jaiswal, Liran I. Shlush Tags: Perspective Source Type: research

Evolution patterns of paroxysmal nocturnal hemoglobinuria clone and clinical implications in acquired bone marrow failure
The Dameshek's riddle raised by Dr. Dameshek in 1967 focused on a provocative question: what do aplastic anemia (AA), paroxysmal nocturnal hemoglobinuria (PNH) and "hypoplastic" leukemia have in common? [1]. The riddle was based on the following clinical observation: frequent development of PNH in AA patients; the overlap between the symptomatic PNH and AA; the similar high prevalence of both PNH and AA in the Orient. In 1992, Young addressed the issue and restated the riddle relevant to the hematopoietic cell clonality, a single "insult" of PNH clone occurring in AA, PNH, and a pre-leukemic condition o...
Source: Experimental Hematology - August 28, 2019 Category: Hematology Authors: Yu Lian, Jun Shi, Neng Nie, Zhendong Huang, Yingqi Shao, Jing Zhang, Jinbo Huang, Xingxin Li, Meili Ge, Peng Jin, Min Wang, Yizhou Zheng Source Type: research

CTLA4Ig-based reduced intensity conditioning and donor lymphocyte infusions for haploidentical transplantation in refractory aggressive B-cell lymphoma relapsing after an autograft: Early results from a pilot study
The outcome of patients with refractory aggressive B-cell lymphoma (R-ABCL), namely, diffuse large B-cell lymphoma (DLBCL), primary mediastinal (thymic) large B-cell lymphoma (PMBCL) and mantle cell lymphoma (MCL) with a high proliferative index, who relapse after an autologous (auto) hematopoietic cell transplantation (HCT), is extremely poor, even with an allogeneic HCT. The key factors influencing the outcome in relapsed ABCL are sensitivity to chemotherapy and time to relapse following an auto-HCT [1]. (Source: Experimental Hematology)
Source: Experimental Hematology - August 23, 2019 Category: Hematology Authors: Sarita Rani Jaiswal, Hema Malini Aiyer, Garima Rawat, Arun Gera, Suparno Chakrabarti Tags: Regular Submission Source Type: research

CTLA4Ig Based Reduced Intensity Conditioning and Donor Lymphocyte Infusions For Haploidentical Transplantation In Refractory Aggressive B Cell Lymphoma Relapsing after An Autograft: Early Results From A Pilot Study
The outcome of patients with refractory aggressive B cell lymphoma (R-ABCL), namely diffuse large B cell lymphoma (DLBCL), Primary Mediastinal (Thymic) Large B-cell lymphoma (PMBCL) and mantle cell lymphoma (MCL) with high proliferative index, who relapse after an autologous (auto) hematopoietic cell transplantation (HCT), is extremely poor, even with an allogeneic HCT. The key factors influencing the outcome in relapsed ABCL is sensitivity to chemotherapy and time to relapse following an auto-HCT [1]. (Source: Experimental Hematology)
Source: Experimental Hematology - August 23, 2019 Category: Hematology Authors: Sarita Rani Jaiswal, Hema Malini Aiyer, Garima Rawat, Arun Gera, Suparno Chakrabarti Source Type: research

Auer rod-like inclusions in the cytoplasm of B-cell lymphoma cells with bone marrow infiltration
Auer rods were first described in the cytoplasm of leukemia blasts by John Auer in 1906. Auer rods are commonly seen in myeloid progenitors, and serve as a diagnostic morphological feature of acute myeloid leukemia (AML) [1]. The differential diagnosis of hematopoietic neoplasms relies on the detection of cytoplasmic inclusions resembling Auer rods. Auer rod-like inclusions have been described in multiple myeloma [2], prolymphocytic leukemia (PLL) [3], B-cell acute lymphoblastic leukemia [4], chronic lymphocytic leukemia [4], splenic lymphoma [5] and nodal marginal zone lymphoma [6], which are quite distinct from the needl...
Source: Experimental Hematology - August 20, 2019 Category: Hematology Authors: Zhanxi Gao, Fang Cui, Mei Liu, Yukai Guo, Yuhong Hu, Min Shi Tags: Brief Communication Source Type: research

Bmi1 restricts the adipogenic differentiation of bone marrow stromal cells to maintain the integrity of the hematopoietic stem cell niche
Hematopoietic stem cells (HSCs) self-renew and differentiate into all blood types, thereby sustaining hematopoiesis during life. HSC niches are specialized bone marrow (BM) microenvironments that maintain HSCs and regulate their functions. The location of HSCs in BM remains controversial; however, recent studies using BM imaging showed that most HSCs reside adjacent to sinusoidal blood vessels, arterioles, and transition zone vessels, suggesting that HSCs are mostly maintained in the perivascular niche [1-5]. (Source: Experimental Hematology)
Source: Experimental Hematology - August 11, 2019 Category: Hematology Authors: Yuko Kato, Li-Bo Hou, Satoru Miyagi, Eriko Nitta, Kazumasa Aoyama, Daisuke Shinoda, Satoshi Yamazaki, Wakako Kuribayashi, Yusuke Isshiki, Shuhei Koide, Sha Si, Atsunori Saraya, Yumi Matsuzaki, Maarten van Lohuizen, Atsushi Iwama Tags: Research Articles Source Type: research

Dietary supplementation with sulforaphane attenuates liver damage and heme overload in a sickle cell disease murine model
Sickle cell disease (SCD) is a recessive Mendelian hemoglobinopathy affecting millions of people worldwide and remains one of the major causes of morbidity and mortality globally. SCD results from a single amino acid substitution at the 6th residue of β-globin [1]. Hence, the mutant hemoglobin produced is called hemoglobin S (HbS). When deoxygenated, HbS molecules polymerize and form the characteristic sickled red blood cells (RBCs) [2]. Recurrent sickling of RBCs alters their membrane structure, making them highly adhesive to the vascular wall and other inflammatory cells, which facilitates intermittent vaso-occlusio...
Source: Experimental Hematology - August 9, 2019 Category: Hematology Authors: Harit Panda, Nadine Keleku-Lukwete, Ayumi Kuga, Nobuo Fuke, Hiroyuki Suganuma, Mikiko Suzuki, Masayuki Yamamoto Source Type: research

Fetal liver Mll-AF4+ hematopoietic stem and progenitor cells respond directly to poly(I:C), but not to a single maternal immune activation
T(4;11) MLL-AF4 acute lymphoblastic leukemia is an aggressive subtype of infant and pediatric leukemia that originates in utero, with monozygotic twin studies having shown a 100% penetrance [1]. We are starting to gain more insights into how the disease develops through the use of pre-leukemia and leukemia mouse models [2-8]. Using a pre-leukemia mouse model, in which expression of Mll-AF4 initiates in all definitive hematopoietic cells formed during embryonic development (Mll-AF4 invertor mouse crossed with VEC-Cre), we have previously identified the fetal liver as the starting point of MLL-AF4-driven leukemogenesis [4,7]...
Source: Experimental Hematology - August 2, 2019 Category: Hematology Authors: Camille Malouf, Katrin Ottersbach Source Type: research

Author Index
(Source: Experimental Hematology)
Source: Experimental Hematology - August 1, 2019 Category: Hematology Source Type: research

1001 - primitive sensing and communication mechanisms regulating bone marrow
Studying bone marrow hematopoiesis has provided insights into how heterologous cells interrelate to dynamically regulate production of mature effector cells. The interactions that have been defined have largely been at the level of receptor proteins and signaling pathways that are common among mammalian tissues but are likely to be late in evolutionary time. We hypothesized that organized complex tissues like bone marrow also retain primitive means of communicating from early metazoan ancestors. (Source: Experimental Hematology)
Source: Experimental Hematology - August 1, 2019 Category: Hematology Authors: David Scadden Source Type: research

1002 - looping and leukaemia: alterations in dna topology shape malignant transcriptional programmes
Cancer is initiated and maintained by malignant transcriptional programmes, with acute myeloid leukaemia (AML) an exemplar of this process. AML is associated with mutations in multiple transcriptional and epigenetic regulators and aberrant expression patterns in AML can be used to classify and provide prognostic and predictive data to personalise therapy and improve patient outcomes. However, while transcriptional outputs resulting from these lesions have been described in both model systems and patient samples, the mechanistic detail of how chromatin accessibility, chromatin activity and three dimensional DNA topology cha...
Source: Experimental Hematology - August 1, 2019 Category: Hematology Authors: Brian Huntly Source Type: research

1003 - understanding and targeting the stem cell origins of myeloid malignancies
Relapse and malignant progression continue to be the most common causes of death in myelodysplastic syndromes (MDS) acute myeloid leukemia (AML) and many other cancers. Recent evidence has shown that a molecularly diverse pool of hematopoietic stem cells lead to the formation of pre-cancerous/pre-leukemic stem cells that play a pivotal role not only in disease origination but also in relapse. While the existence and essentiality of such pre-cancerous cell states including pre-MDS-SC and pre-AML-SC has been demonstrated in mice and humans, still very little is known about the molecular mechanisms driving their formation and...
Source: Experimental Hematology - August 1, 2019 Category: Hematology Authors: Ulrich Steidl Source Type: research

1004 - how do srsf2p95h mutations lead to myelodysplastic/myeloproliferative syndrome (mds/mpn)?
SRSF2 P95 mutations are prevalent in myelodysplastic (MDS) and myelodysplastic/myeloproliferative (MDS/MPN) syndromes. They occur early in the course of the disease, are positively selected during disease progression and are associated with poor outcomes. Understanding how founder mutations such as SRSF2 modifies haematopoiesis and ultimately contributes to the development of myeloid bias and MDS/MPN will be critical to understanding the initiation and maintenance of these cancers. We have generated a conditional murine Srsf2P95H mutation model, where the temporal and cell type specific expression of the P95H mutation can ...
Source: Experimental Hematology - August 1, 2019 Category: Hematology Authors: Carl Walkley Source Type: research

1005 - the identification of a peri-arteriolar niche for lymphoid progenitors and osteogenic progenitors in the bone marrow
Leptin Receptor-expressing (LepR+) stromal cells in adult bone marrow are highly enriched for skeletal stem cells and are the main source of osteoblasts and adipocytes in addition to SCF and Cxcl12 for HSC maintenance (Nature 481:457; Nature 495:231; Cell Stem Cell 15:154). We discovered that a subset of these cells produce a previously uncharacterized bone-forming growth factor, Clec11a/Osteolectin, which promotes the osteogenic differentiation of LepR+ cells and is required for the maintenance of adult skeletal bone mass (eLife 5:e18782). (Source: Experimental Hematology)
Source: Experimental Hematology - August 1, 2019 Category: Hematology Authors: Sean Morrison, Bo Shen Source Type: research

1006 - key roles of hoxa1 in hscs and myelodysplastic syndromes
Homeobox a1 (Hoxa1) has 2 different isoforms: a full-length homeodomain-containing Hoxa1 (Hoxa1-FL) and a truncated Hoxa1 (Hoxa1-T), which is spliced within exon 1 of Hoxa1-FL and lacks the homeodomain. Hoxa1-FL and Hoxa1-T are differentially expressed in distinct populations of hematopoietic cells. To examine their roles in hematopoiesis, we retrovirally overexpressed WT-Hoxa1 (which generates both isoforms) or Hoxa1-T in murine bone marrow (BM). We also generated a mutant Hoxa1 (MUT-Hoxa1), which expresses Hoxa1-FL but not Hoxa1-T, by site-directed mutagenesis. (Source: Experimental Hematology)
Source: Experimental Hematology - August 1, 2019 Category: Hematology Authors: Louise Purton Source Type: research

1007 - metabolic restoration of the aged hematopoietic stem cell microenvironment
Blood production depends relies on haematopoietic stem cells (HSC) regenerating and differentiating into all mature cell lineages. With age, HSC lose regenerative capacity and become metabolically more active, resulting in an expanded HSC pool coinciding with skewed lineage differentiation. Ultimately this can lead to anaemia, marrow failure or leukaemia. A contributing factor to impaired hematopoiesis with age is the loss of key nutrients in the microenvironment involved in the maintenance of HSC metabolic stability. (Source: Experimental Hematology)
Source: Experimental Hematology - August 1, 2019 Category: Hematology Authors: Susie Nilsson Source Type: research

1008 - changing neighbours: bone marrow remodelling during aging and age-related myeloproliferative disorders
Haematopoietic stem cells residing in the bone marrow accumulate during ageing but are functionally impaired. However, the role of haematopoietic-stem-cell-intrinsic and -extrinsic ageing mechanisms remains debated. Myeloid malignancies are more frequent in the elderly, but whether changes in the aged haematopoietic stem cells and/or their microenvironment predispose to these malignancies remains unclear. In the first part of the talk, unpublished evidence will be presented indicating that the bone marrow microenvironment promotes haematopoietic ageing, both during physiology and in premature, pathological haematopoietic a...
Source: Experimental Hematology - August 1, 2019 Category: Hematology Authors: Simon Mendez-Ferrer Source Type: research

1009 - an ectoderm-derived myeloid-like cell population functions as antigen transporters for langerhans cells in zebrafish epidermis
In this study, we report the identification and characertization of a previously unappreciated myeloid-like cells population, which we refer to as metapgocytes, in zebrafish epidermis. We show that metaphocytes are of ectodermal origin and share a high degree of similarity with Langerhans cells in transcriptome, morphology and anatomic location. Remarkably, unlike Langerhans cells, metaphocytes respond to neither tissue injury nor bacterial infection, but rather sample soluble antigens from external enviroment through transepithelial protrusions and subsequently transfer the antigens to Langerhans cells via apoptosis-phago...
Source: Experimental Hematology - August 1, 2019 Category: Hematology Authors: Zilong Wen, Xi Lin, Qiuxia Zhou, Changlong Zhao, Guanzhen Lin, Jin Xu Source Type: research

1010 - characterizing hoxa-expressing endothelial and haematopoietic populations derived from human pluripotent stem cells
Haematopoietic stem cell (HSC) transplantation is a key therapy for patients with leukaemia or bone marrow failure. Repopulating HSCs derived from human pluripotent stem cells (hPSCs) would provide a source of blood stem cells for many patients who might benefit from this therapy but lack a suitable donor.Success is contingent on the development of hPSC differentiation protocols that generate and support the developmental continuum from correctly patterned haemogenic endothelium to the emerging preHSCs, and their subsequent maturation to repopulating (r) HSCs. (Source: Experimental Hematology)
Source: Experimental Hematology - August 1, 2019 Category: Hematology Authors: Elizabeth Ng, Jasna Kusur, Tanya Labonne, Edouard Stanley, Andrew Elefanty Source Type: research

1011 - the role of mutant p53 in tumor development and the response of malignant cells to anti-cancer therapeutics
p53 is a highly potent tumour suppressor that acts through activation of several biological processes, including apoptotic cell death, cell growth arrest and cell senescence. In accordance with its critical role in tumour suppression, the p53 gene is the most frequently mutated gene in human cancers. Mutant p53 cancers are usually relatively resistant to chemotherapeutic drugs and such patients therefore often have a poor prognosis. Despite several decades of research into the functions of wild-type (wt) p53 in normal cells and mutant p53 in tumour cells, we still do not have a clear understanding of how mutations in p53 c...
Source: Experimental Hematology - August 1, 2019 Category: Hematology Authors: Gemma Kelly Source Type: research

1012 - mitochondrial dynamics, damage, and inflammatory signalling
The mitochondrial (or intrinsic) apoptosis pathway plays an essential role in the development, survival and clearance of many hematopoietic lineages. It can be activated by pathophysiological insults such as anti-cancer therapy and infection, and its suppression is regarded as one of the hallmarks of cancer. The first drug that specifically targets the pathway, Venetoclax, was approved for use in chronic lymphocytic leukemia in 2016. In recent years, we and others have uncovered a link between mitochondrial apoptosis and innate immune signalling, demonstrating that the apoptotic caspase cascade (which functions downstream ...
Source: Experimental Hematology - August 1, 2019 Category: Hematology Authors: Benjamin Kile Source Type: research

1013 - chromatin proteins in haematopoietic stem cells and haematological malignancies
A major focus of our work is the role of chromatin modifying complexes in normal haematopoiesis and in leukaemia. For example, somatically acquired mutations in the plant homeodomain finger 6 gene (PHF6) frequently occur in haematopoietic malignancies and often coincide with ectopic expression of TLX3. However, there is no functional evidence to demonstrate whether these mutations contribute to tumourigenesis. Similarly, the role of PHF6 in haematopoiesis is unknown. We found that Phf6 deletion in mice resulted in a reduced number of haematopoietic stem cells (HSCs), an increased number of haematopoietic progenitor cells, ...
Source: Experimental Hematology - August 1, 2019 Category: Hematology Authors: Anne Voss, Tim Thomas, Helen McRae Source Type: research

1014 - the prc2 co-factor jarid2 is a key regulator of normal and neoplastic hematopoiesis
The property of self-renewal sustains the hematopoietic stem cell (HSC) pool for the lifetime of an organism. While tremendous progress has been made into understanding specific genes and pathways that regulate HSC self-renewal, the molecular mechanisms by which self-renewal is repressed in downstream hematopoietic progenitors is largely unknown. Understanding the mechanisms that restrict self-renewal potential in hematopoietic progenitors may allow augmentation of limited sources of HSCs to improve bone marrow transplantation, or enhance self-renewal potential of progenitor cells in diseases associated with HSC depletion ...
Source: Experimental Hematology - August 1, 2019 Category: Hematology Authors: Grant Challen Source Type: research

1015 - inhibition of endothelial mtor drives hematopoietic stem cell aging
Aging leads to a decline in hematopoietic stem cell (HSC) function. While some of these age-related changes reflect intrinsic alterations within HSCs, recent findings suggest that signals from the bone marrow (BM) microenvironment, in particular the BM vascular niche, might play a crucial role in regulating HSC aging. To this end, we recently discovered that aging of BM endothelial cells (BMECs) leads to an altered molecular crosstalk between the BMEC niche and HSCs that instructs young HSCs to behave as aged HSCs. (Source: Experimental Hematology)
Source: Experimental Hematology - August 1, 2019 Category: Hematology Authors: Jason Butler, Pradeep Ramalingam Source Type: research

1016 - early diagnosis and prevention of aml
Acute myeloid leukemia (AML) is a devastating disease especially among the elderly. Most AML cases present after a chronic latent phase of age-related clonal hematopoiesis (ARCH), yet while the prevalence of ARCH among the elderly is high ( ∼30%), AML remains a rare event. Recently, we succeeded to predict pre-AML cases seven years prior to diagnosis with a sensitivity of ∼40% and a specificity of 98.5%. The most accurate early diagnosis was for cases with mutations in the spliceosome. For these patients we have several drugs that might be useful in AML prevention and clinical trials for AML prevention are under pr...
Source: Experimental Hematology - August 1, 2019 Category: Hematology Authors: Liran Shlush Source Type: research

1017 - translational lessons in optimizing clinical use of bh3 mimetics to treat hematological malignancies
Oncogenic mutations impose stresses on cells which normally would trigger apoptosis. Consequently, many haematological malignancies harbour aberrations that circumvent this, most prominently dysfunction of the TP53 pathway and dysregulation of the BCL2 protein family. The prosurvival proteins BCL2 and MCL1 are commonly highly expressed in diseases like CLL, lymphomas, AML and myeloma. BH3-mimetics are a novel class of anti-cancer drugs which mimic the natural antagonists of the prosurvival proteins and operate downstream of TP53. (Source: Experimental Hematology)
Source: Experimental Hematology - August 1, 2019 Category: Hematology Authors: Andrew Roberts Source Type: research

1018 - cd97 is a critical regulator of acute myeloid leukemia stem cell function
Despite advances in our understanding of the genetic origins of acute myeloid leukemia (AML), treatment options have remained essentially unchanged for 30 years, and clinical outcomes remain poor. AML is maintained by leukemia stem cells (LSCs), which are critical for disease maintenance as well as re-initiating disease after therapy. We previously identified novel markers and therapeutic targets in AML and MDS by comparing the transcriptomes of stem cells to normal purified HSCs, leading to the identification of CD99 as an antigen selectively expressed on LSCs.  Moreover, novel monoclonal antibodies against CD99 exer...
Source: Experimental Hematology - August 1, 2019 Category: Hematology Authors: Christopher Park, Gaelle Martin, Nainita Roy, Sohini Chakraborty, Alexis Desrichard, Stephen chung, Carolien Woolthuis, Wenhuo Hu, Iryna berezniuk, Francine Garrett-Bakelman, Jorg Hamann, sean Devlin, Timothy chan Source Type: research

1019 - deconvolution of hematopoietic commitment decisions by genome-wide analysis of progressive dna methylation changes
Advances in single cell transcriptome analyses have resulted in the derivation of new models to describe the hierarchical organization of the mammalian hematopoietic system. While such an approach appears to be effective at discerning the trajectory of differentiation from hematopoietic stem cells (HSCs) to a given mature lineage, it remains a challenge to identify definitive points where specific lineage fates become restricted. 5-MeC is a stable epigenetic modification, whose remodeling is integral to the process of enforcing lineage-restricted gene expression programs. (Source: Experimental Hematology)
Source: Experimental Hematology - August 1, 2019 Category: Hematology Authors: Michael Milsom Source Type: research

1020 - new insights into inflammasome signalling and function during inflammation
Inflammasomes are signalling hubs that assemble in response to cell stress or microbial infection, and provide an activation platform for the zymogen protease, caspase-1. Upon activation, caspase-1 triggers the maturation and secretion of potent pro-inflammatory mediators (interleukin-1beta and -18) and induces cell lysis, culminating in the activation of the immune system and antimicrobial defence. Inflammasome signalling can, however, also drive pathology in a range of human auto-inflammatory, inflammatory, metabolic and neurodegenerative diseases. (Source: Experimental Hematology)
Source: Experimental Hematology - August 1, 2019 Category: Hematology Authors: Kate Schroder, Dave Boucher, Rebecca Coll Source Type: research

1021 - endothelial niche adhesive regulation of normal and malignant haematopoietic stem cells
Our laboratory previously identified a novel role for vascular cell adhesion molecules in promoting the awakening of dormant Haematopoietic Stem Cells (HSCs) in the bone marrow (BM) (Nat Med 2012). Now we show vascular niche adhesion can trigger a cascade of intracellular signalling events that can metabolically and transcriptionally reprogram a cell. For bone marrow (BM) Haematopoietic Stem and Progenitor Cells (HSPC) these open new avenues to tailor immune response and recovery during stress.Malignant cells also take advantage of these pathways. (Source: Experimental Hematology)
Source: Experimental Hematology - August 1, 2019 Category: Hematology Authors: Ingrid Winkler Source Type: research

1022 - systematic genetic dissection of the hematopoietic stem cell niche in the fetal liver
The liver is the main hematopoietic organ and the site of hematopoietic stem cell (HSC) expansion and maturation in mammalian fetuses. However, little is known about the nature of the HSC niche in the developing liver in vivo. Here, we genetically dissected the cellular components of the developing liver niche by determining the cellular sources of a key HSC niche factor, stem cell factor (SCF). We found that Scf was primarily expressed by endothelial cells and hepatic stellate cells. Conditional deletion of Scf from hematopoietic cells, hepatocytes, Ng2+ cells or endothelial cells did not affect HSC number or function. (S...
Source: Experimental Hematology - August 1, 2019 Category: Hematology Authors: Lei Ding, Yeojin Lee, Juliana Leslie, Ying Yang Source Type: research

1023 - regeneration of t lymphopoiesis from pluripotent stem cells by defined factors
Regarding the unlimited source and gene-editing advantages of pluripotent stem cells (PSC), generating functional T lymphocytes from PSC provides an ideal approach for broadening T cell-based translational applications. In the presence of Notch ligands, PSC can conventionally generate induced T cell progenitors, which reportedly lack thymus-homing capacity in vivo. Using an inducible tandem-knock-in strategy and a functional screening by transplantation setting, we screened the combinatory effects of the essential transcription factors, which are abundantly expressed in developmental pre-HSC but absent in induced hemogenic...
Source: Experimental Hematology - August 1, 2019 Category: Hematology Authors: Jinyong Wang, Rongqun Guo, Fangxiao Hu, Qitong Weng, Cui Lv, Hongling Wu, Lijuan Liu, Bing Liu Source Type: research

1024 - epigenetic control of myeloid cell development by the transcription factor irf8
Differentiation of hematopoietic stem and progenitor cells to various types of blood cells is a process of establishing cell type-specific gene expression patterns. We have been investigating the mechanism of myeloid cell development from a viewpoint of gene expression control by transcription factors, particularly IRF8. In Irf8 –/– mice, mononuclear phagocyte progenitors are accumulated, and these progenitors do not efficiently differentiate into monocytes (Mos) or dendritic cells (DCs) but instead, give rise to a large number of neutrophils. (Source: Experimental Hematology)
Source: Experimental Hematology - August 1, 2019 Category: Hematology Authors: Tomohiko Tamura Source Type: research

1025 - long-term single-cell quantification: new tools for old questions
Despite intensive research, surprisingly many long-standing questions in cell research remain disputed. One major reason is the fact that we usually analyze only populations of cells - rather than individual cells – and at very few time points of an experiment – rather than continuously. We therefore develop imaging systems and software to image, segment and track cells long-term, and to quantify e.g. divisional history, position, interaction, and protein expression or activity of all individual cells ove r many generations. (Source: Experimental Hematology)
Source: Experimental Hematology - August 1, 2019 Category: Hematology Authors: Timm Schroeder Source Type: research

1026 - jak/stat signalling, stem cell subversion and myeloid malignancies
Our research focuses on the mechanisms whereby blood stem cells are subverted during the genesis of haematological malignancies.   We have increasingly concentrated on JAK/STAT signalling which is dysregulated in many cancers and plays a key role in multiple stem cell systems.  In particular we have explored the molecular and cellular pathogenesis of a group of pre-leukaemic disorders, the myeloproliferative neoplasms (MPNs ), in studies which have spanned basic, translational and clinical research. (Source: Experimental Hematology)
Source: Experimental Hematology - August 1, 2019 Category: Hematology Authors: Tony Green Source Type: research

1027 - development of hematopoietic stem cells
In vertebrate embryos, hematopoietic stem cells (HSCs) are generated from a subset of the aortic endothelium, the hemogenic endothelium, via a process called endothelial-to-hematopoietic transition (EHT). In our studies aimed at obtaining a mechanistic insight into EHT we have identified cell type and stage specific enhancers of Runx1 – a critical regulator of EHT – and generated transgenic enhancer-reporter mouse models to isolate hemogenic endothelium. Functional and molecular analysis of hemogenic endothelium established that these cells undergo dynamic changes early in development, rewriting the timeline of...
Source: Experimental Hematology - August 1, 2019 Category: Hematology Authors: Marella de Bruijn Source Type: research

1028 - mitochondria metabolism in quiescent and cycling hematopoietic stem cells
Cellular metabolism is an area of recent intense research interest. However, the metabolic requirements for adaptations of stem cells to their niches remain largely unaddressed. The cell metabolism may be quite different in quiescent and cycling HSCs.Most of the hematopoietic stem cells (HSCs) within the bone marrow show quiescent state. By contrast, upon stress hematopoiesis, HSCs actively divide to regenerate hematopoietic system with the appropriate balance between self-renewal and differentiation divisions. (Source: Experimental Hematology)
Source: Experimental Hematology - August 1, 2019 Category: Hematology Authors: Toshio Suda Source Type: research