The structure of the hematopoietic system can explain chronic myeloid leukemia progression.

Almost all cancer types share the hallmarks of cancer and a similar tumor formation: fueled by stochastic mutations in somatic cells. In case of chronic myeloid leukemia (CML), this evolutionary process can be tracked from an asymptomatic long-lasting chronic phase to a final rapidly evolving blast phase. Somatic evolution in CML occurs in the context of healthy blood production, a hierarchical process of cell division; initiated by stem cells that self-renew and differentiate to produce mature blood cells. Here we introduce a general model of hierarchical cell division explaining the particular progression of CML as resulting from the structure of the hematopoietic system. Driver mutations confer a growth advantage to the cells carrying them, for instance, the BCR::ABL1 gene, which also acts as a marker for CML. We investigated the relation of the BCR::ABL1 mutation strength to the hematopoietic stem cell division rate by employing computer simulations and fitting the model parameters to the reported median duration for the chronic and accelerated phases. Our results demonstrate that driver mutations (additional to the BCR::ABL1 mutation) are necessary to explain CML progression if stem cells divide sufficiently slowly. We observed that the number of mutations accumulated by cells at the more differentiated levels of the hierarchy is not affected by driver mutations present in the stem cells. Our results shed light on somatic evolution in a hierarchical tissue and show that the clinical hallmarks of CML progression result from the structural characteristics of blood production.

[The 5th edition of the WHO classification of lymphoid neoplasms-an overview]. / Die 5. Ausgabe der WHO-Klassifikation lymphatischer Neoplasien ­ ein Überblick.

The "Blue Book" of the WHO classification of haematolymphoid tumours is the worldwide accepted reference in malignant tumours of the myeloid and lymphoid system. The REAL classification of 1994 [2] laid the foundations for the WHO volumes, with continous development and specification to date [3, 5, 6]. In the 5th edition of the classification to be released this year, new insights concerning the pathogenesis and molecular genetics, and new concepts regarding the taxonomic basis of the classification are included. Overviews of the changes and new aspects of the 5th edition of the classification of haematolymphoid tumours (WHO-HAEM5) have recently been published [1, 4]. Overall, 420 authors participated on the WHO-HAEM5, among them numerous members of the large international societies for haematopathology, the European Association for Haematopathology (EAHP) and the Society for Hematopathology (SH). The WHO-HAEM5 was developed in a multidisciplinary setting in numerous online meetings with haematopathologists, haematologists, oncologists, geneticists, epidemiologists and molecular biologists. In extensive discussions, harmonisation of chapters and with the other volumes of the 5th series was sought. For implementation of clinical aspects, a clinical advisory board was consulted. The new classification constitutes a systematic update of former classifications. As has been implemented earlier, the entities are presented in a hierarchical order: category (e.g. mature B­cell neoplasm), family/class (e.g. diffuse large B­cell lymphoma, DLBCL), entity (e.g. DLBCL, not otherwise specified, NOS) and subtype (e.g. DLBCL, NOS, GCB-type). Similar to the 5th editions of other WHO classifications, at the end of each chapter, a list of "essential" diagnostic criteria representing minimal criteria to establish the diagnosis and "desirable" diagnostic criteria are given in order to further confirm and specify the diagnosis.

Mitigation of total body irradiation-induced mortality and hematopoietic injury of mice by a thrombopoietin mimetic (JNJ-26366821).

The threat of a nuclear attack has increased in recent years highlighting the benefit of developing additional therapies for the treatment of victims suffering from Acute Radiation Syndrome (ARS). In this work, we evaluated the impact of a PEGylated thrombopoietin mimetic peptide, JNJ-26366821, on the mortality and hematopoietic effects associated with ARS in mice exposed to lethal doses of total body irradiation (TBI). JNJ-26366821 was efficacious as a mitigator of mortality and thrombocytopenia associated with ARS in both CD2F1 and C57BL/6 mice exposed to TBI from a cobalt-60 gamma-ray source. Single administration of doses ranging from 0.3 to 1 mg/kg, given 4, 8, 12 or 24 h post-TBI (LD70 dose) increased survival by 30-90% as compared to saline control treatment. At the conclusion of the 30-day study, significant increases in bone marrow colony forming units and megakaryocytes were observed in animals administered JNJ-26366821 compared to those administered saline. In addition, enhanced recovery of FLT3-L levels was observed in JNJ-26366821-treated animals. Probit analysis of survival in the JNJ-26366821- and saline-treated cohorts revealed a dose reduction factor of 1.113 and significant increases in survival for up to 6 months following irradiation. These results support the potential use of JNJ-26366821 as a medical countermeasure for treatment of acute TBI exposure in case of a radiological/nuclear event when administered from 4 to 24 h post-TBI.

Improved nonclinical safety profile of a novel, highly selective inhibitor of the immunoproteasome subunit LMP7 (M3258).

M3258 is the first selective inhibitor of the immunoproteasome subunit LMP7 (Large multifunctional protease 7) in early clinical development with the potential to improve therapeutic utility in patients of multiple myeloma (MM) or other hematological malignancies. Safety pharmacology studies with M3258 did not reveal any functional impairments of the cardiovascular system in several in vitro tests employing human cardiomyocytes and cardiac ion channels (including hERG), guinea pig heart refractory period and force contraction, and rat aortic contraction as well as in cardiovascular function tests in dogs. Following single dose M3258 administration to rats, no changes were observed on respiratory function by using whole body plethysmography, nor did it change (neuro)behavioral parameters in a battery of tests. Based on pivotal 4-week toxicity studies with daily oral dosing of M3258, the identified key target organs of toxicity were limited to the lympho-hematopoietic system in rats and dogs, and to the intestine with its local lymphoid tissues in dogs only. Importantly, the stomach, nervous system, heart, lungs, and kidneys, that may be part of clinically relevant toxicities as reported for pan-proteasome inhibitors, were spared with M3258. Therefore, it is anticipated that by targeting highly selective and potent inhibition of LMP7, the resulting favorable safety profile of M3258 together with the maintained potent anti-tumor activity as previously reported in mouse MM xenograft models, may translate into an improved benefit-risk profile in MM patients.

Effects of captopril against radiation injuries in the Göttingen minipig model of hematopoietic-acute radiation syndrome.

Our laboratory has demonstrated that captopril, an angiotensin converting enzyme inhibitor, mitigates hematopoietic injury following total body irradiation in mice. Improved survival in mice is correlated with improved recovery of mature blood cells and bone marrow, reduction of radiation-induced inflammation, and suppression of radiation coagulopathy. Here we investigated the effects of captopril treatment against radiation injuries in the Göttingen mini pig model of Hematopoietic-Acute Radiation Syndrome (H-ARS). Minipigs were given captopril orally (0.96 mg/kg) twice daily for 12 days following total body irradiation (60Co 1.79 Gy, 0.42-0.48 Gy/min). Blood was drawn over a time course following irradiation, and tissue samples were collected at euthanasia (32-35 days post-irradiation). We observed improved survival with captopril treatment, with survival rates of 62.5% in vehicle treated and 87.5% in captopril treated group. Additionally, captopril significantly improved recovery of peripheral blood mononuclear cells, and a trend toward improvement in recovery of red blood cells and platelets. Captopril significantly reduced radiation-induced expression of cytokines erythropoietin and granulocyte-macrophage colony-stimulating factor and suppressed radiation-induced acute-phase inflammatory response cytokine serum amyloid protein A. Using quantitative-RT-PCR to monitor bone marrow recovery, we observed significant suppression of radiation-induced expression of redox stress genes and improved hematopoietic cytokine expression. Our findings suggest that captopril activities in the Göttingen minipig model of hematopoietic-acute radiation syndrome reflect findings in the murine model.

Innate and adaptive immunity: the understudied driving force of heart valve disease.

Calcific aortic valve disease (CAVD), and its clinical manifestation that is calcific aortic valve stenosis, is the leading cause for valve disease within the developed world, with no current pharmacological treatment available to delay or halt its progression. Characterized by progressive fibrotic remodelling and subsequent pathogenic mineralization of the valve leaflets, valve disease affects 2.5% of the western population, thus highlighting the need for urgent intervention. Whilst the pathobiology of valve disease is complex, involving genetic factors, lipid infiltration, and oxidative damage, the immune system is now being accepted to play a crucial role in pathogenesis and disease continuation. No longer considered a passive degenerative disease, CAVD is understood to be an active inflammatory process, involving a multitude of pro-inflammatory mechanisms, with both the adaptive and the innate immune system underpinning these complex mechanisms. Within the valve, 15% of cells evolve from haemopoietic origin, and this number greatly expands following inflammation, as macrophages, T lymphocytes, B lymphocytes, and innate immune cells infiltrate the valve, promoting further inflammation. Whether chronic immune infiltration or pathogenic clonal expansion of immune cells within the valve or a combination of the two is responsible for disease progression, it is clear that greater understanding of the immune systems role in valve disease is required to inform future treatment strategies for control of CAVD development.

Immunopathogenesis of hematopoietic tissues in response to Vibrio parahaemolyticus (VPAHPND) infection in Macrobrachium rosenbergii.

In crustacean, hemocytes are known as crucial components of crustaceans' innate immunity against pathogens. Drastic hemocytes reduction during infectious disease is apparently related to disease severity and calls for a health status evaluation and aquaculture management. The molecular pathogenesis of hemocytes loss during bacterial infection was elucidated with VPAHPND challenged in M. rosenbergii. We report herein a correlation between hemocyte loss and the pathogenicity and aggressive immune response in hematopoietic tissues of moribund M. rosenbergii. In this study, adult freshwater prawn was administered an LC50 dose of VPAHPND; bacterial clearance ensued, and success was reached within 24 h. Hemocytes increased in survival, yet drastically decreased in moribund prawn. Pathological analysis of hematopoietic tissue of moribund prawn showed apparent abnormal signs, including the presence of bacteria, a small number of mitotic cells, cellular swelling, loosening of connective tissue, and karyorrhectic nuclei cells. A significant upregulation of a core apoptotic machinery gene, caspase-3, was detected in hematopoietic tissue of moribund shrimp, but not in those of Escherichia coli DH5α (non-pathogenic bacteria) and VPAHPND survival prawn. The highest level was found in the moribund group, which confirms the occurrence of apoptosis in this hematopoietic tissue. Further, our results suggest that hematopoietic tissue damage may arise from inflammation triggered by an aggressive immune response. Immune activation was indicated by the comparison of immune-related gene expression between controls, E. coli (DH5α)-infected (non-pathogenic), and VPAHPND-infected survival groups with moribund prawn. RT-PCR revealed a significant upregulation of all genes in hematopoietic tissues and hemocytes within 6-12 h and declined by 24 h. This evident related to the almost VPAHPND are clearance in survival and E. coli (DH5α) challenged group in contrast with drastic high expression was determined in moribund group. We conclude that a reduction of renewing circulating hemocytes in fatally VPAHPND-infected prawn was caused by an acute self-destructive immune response by hematopoietic cells.

Single-Dose Administration of Recombinant Human Thrombopoietin Mitigates Total Body Irradiation-Induced Hematopoietic System Injury in Mice and Nonhuman Primates.

PURPOSE: Recombinant human thrombopoietin (rhTPO) has been evaluated as a therapeutic intervention for radiation-induced myelosuppression. However, the immunogenicity induced by a repeated-dosing strategy raises concerns about the therapeutic use of rhTPO. In this study, single-dose administration of rhTPO was evaluated for efficacy in the hematopoietic response and survival effect on mice and nonhuman primates exposed to total body irradiation (TBI). METHODS AND MATERIALS: Survival of lethally (9.0 Gy) irradiated C57BL/6J male mice was observed for 30 days after irradiation. Hematologic evaluations were performed on C57BL/6J male mice given a sublethal dose of radiation (6.5 Gy). Furthermore, in sublethally irradiated mice, we performed bone marrow (BM) histologic evaluation and evaluated BM-derived clonogenic activity. Next, the proportion and number of hematopoietic stem cells (HSCs) were analyzed. Competitive repopulation experiments were conducted to assess the multilineage engraftment of irradiated HSCs after BM transplantation. Flow cytometry was used to evaluate DNA damage, cell apoptosis, and cell cycle stage in HSCs after irradiation. Finally, we evaluated the efficacy of a single dose of rhTPO administered after 7 Gy TBI in male and female rhesus monkeys. RESULTS: A single administration of rhTPO 2 hours after irradiation significantly mitigated TBI-induced death in mice. rhTPO promoted multilineage hematopoietic recovery, increasing peripheral blood cell counts, BM cellularity, and BM colony-forming ability. rhTPO administration led to an accelerated recovery of BM HSC frequency and multilineage engraftment after transplantation. rhTPO treatment reduced radiation-induced DNA damage and apoptosis and promoted HSC proliferation after TBI. Notably, a single administration of rhTPO significantly promoted multilineage hematopoietic recovery and improved survival in nonhuman primates after TBI. CONCLUSIONS: These findings indicate that early intervention with a single administration of rhTPO may represent a promising and effective radiomitigative strategy for victims of radiation disasters.

A combined prophylactic modality of podophyllotoxin and rutin alleviates radiation induced injuries to the lymphohematopoietic system of mice by modulating cytokines, cell cycle progression, and apoptosis.

The present study was conceptualized to delineate radioprotective efficacy of a formulation G-003M (a combination of podophyllotoxin and rutin) against radiation-induced damage to the lymphohematopoietic system of mice. C57BL/6J mice, treated with G-003M 1 h prior to 9 Gy lethal dose, were assessed for reactive oxygen species (ROS)/nitric oxide (NO) generation, antioxidant alterations, Annexin V/PI and TUNEL staining for apoptosis, modulation of apoptotic proteins, cell proliferation, histological alterations in thymus and cell cycle arrest in bone marrow cells. Induction of granulocyte colony-stimulating factor (G-CSF), granulocytes macrophage colony-stimulating factor (GM-CSF), interleukin-IL-6, IL-10, IL-1α, and IL-1ß in response to G-003M was also evaluated in different groups of mice. Haematopoietic reconstitution with G-003M was explored by examining endogenous spleen colony-forming units (CFU-S) in irradiated animals. G-003M significantly inhibited ROS/NO, malondialdehyde (MDA) and restored cellular antioxidant glutathione in the thymus of irradiated animals. G-003M pre-treatment significantly (p < 0.001) restrained apoptosis in thymocytes via upregulation of Bcl2 and down-regulation of Bax, p53 and caspase-3. Stimulation of cell proliferation and inhibition of apoptosis by G-003M, restored architecture of thymus in irradiated animals within 30 days as evaluated by histological analysis. G-003M arrested cells at the G2/M phase by inducing reversible cell cycle arrest. Peak expression of G-CSF (45-fold) and IL-6 (60-fold) as well as moderate induction of GM-CSF, IL-10, IL-1α by G-003M helped in haematopoietic recovery of irradiated mice. A higher number of endogenous CFU-S in G-003M pre-treated irradiated mice suggested haematopoietic recovery. Data obtained from the current study affirms that G-003M can be proved as a potential radioprotective agent against radiation damage.

Dysregulated Cardiac IGF-1 Signaling and Antioxidant Response Are Associated with Radiation Sensitivity.

Acute exposure to ionizing radiation leads to Hematopoietic Acute Radiation Syndrome (H-ARS). To understand the inter-strain cellular and molecular mechanisms of radiation sensitivity, adult males of two strains of minipig, one with higher radiosensitivity, the Gottingen minipig (GMP), and another strain with comparatively lower radiosensitivity, the Sinclair minipig (SMP), were exposed to total body irradiation (TBI). Since Insulin-like Growth Factor-1 (IGF-1) signaling is associated with radiation sensitivity and regulation of cardiovascular homeostasis, we investigated the link between dysregulation of cardiac IGF-1 signaling and radiosensitivity. The adult male GMP; n = 48, and SMP; n = 24, were irradiated using gamma photons at 1.7-2.3 Gy doses. The animals that survived to day 45 after irradiation were euthanized and termed the survivors. Those animals that were euthanized prior to day 45 post-irradiation due to severe illness or health deterioration were termed the decedents. Cardiac tissue analysis of unirradiated and irradiated animals showed that inter-strain radiosensitivity and survival outcomes in H-ARS are associated with activation status of the cardiac IGF-1 signaling and nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated induction of antioxidant gene expression. Our data link H-ARS with dysregulation of cardiac IGF-1 signaling, and highlight the role of oxidative stress and cardiac antioxidant response in radiation sensitivity.

A missense mutation in the MLKL brace region promotes lethal neonatal inflammation and hematopoietic dysfunction.

MLKL is the essential effector of necroptosis, a form of programmed lytic cell death. We have isolated a mouse strain with a single missense mutation, MlklD139V, that alters the two-helix 'brace' that connects the killer four-helix bundle and regulatory pseudokinase domains. This confers constitutive, RIPK3 independent killing activity to MLKL. Homozygous mutant mice develop lethal postnatal inflammation of the salivary glands and mediastinum. The normal embryonic development of MlklD139V homozygotes until birth, and the absence of any overt phenotype in heterozygotes provides important in vivo precedent for the capacity of cells to clear activated MLKL. These observations offer an important insight into the potential disease-modulating roles of three common human MLKL polymorphisms that encode amino acid substitutions within or adjacent to the brace region. Compound heterozygosity of these variants is found at up to 12-fold the expected frequency in patients that suffer from a pediatric autoinflammatory disease, chronic recurrent multifocal osteomyelitis (CRMO).

Global dynamics of healthy and cancer cells competing in the hematopoietic system.

Stem cells in the bone marrow differentiate to ultimately become mature, functioning blood cells through a tightly regulated process (hematopoiesis) including a stem cell niche interaction and feedback through the immune system. Mutations in a hematopoietic stem cell can create a cancer stem cell leading to a less controlled production of malfunctioning cells in the hematopoietic system. This was mathematically modelled by Andersen et al. (2017) including the dynamic variables: healthy and cancer stem cells and mature cells, dead cells and an immune system response. Here, we apply a quasi steady state approximation to this model to construct a two dimensional model with four algebraic equations denoted the simple cancitis model. The two dynamic variables are the clinically available quantities JAK2V617F allele burden and the number of white blood cells. The simple cancitis model represents the original model very well. Complete phase space analysis of the simple cancitis model is performed, including proving the existence and location of globally attracting steady states. Hence, parameter values from compartments of stem cells, mature cells and immune cells are directly linked to disease and treatment prognosis, showing the crucial importance of early intervention. The simple cancitis model allows for a complete analysis of the long term evolution of trajectories. In particular, the value of the self renewal of the hematopoietic stem cells divided by the self renewal of the cancer stem cells is found to be an important diagnostic marker and perturbing this parameter value at intervention allows the model to reproduce clinical data. Treatment at low cancer cell numbers allows returning to healthy blood production while the same intervention at a later disease stage can lead to eradication of healthy blood producing cells. Assuming the total number of white blood cells is constant in the early cancer phase while the allele burden increases, a one dimensional model is suggested and explicitly solved, including parameters from all original compartments. The solution explicitly shows that exogenous inflammation promotes blood cancer when cancer stem cells reproduce more efficiently than hematopoietic stem cells.

Blood autophagy defect causes accelerated non-hematopoietic organ aging.

Autophagy has been well studied in regulating aging; however, the impact of autophagy in one organ on the aging of other organs has not been documented. In this study, we used a mouse model with deletion of an autophagy-essential gene Atg7 in hematopoietic system to evaluate the intrinsic role of hematopoietic autophagy on the aging of non-hematopoietic organs. We found that autophagy defect in hematopoietic system causes growth retardation and shortened lifespan, along with aging-like phenotypes including hypertrophic heart, lung and spleen, but atrophic thymus and reduced bone mineral density at organismal level. Hematopoietic autophagy defect also causes increased oxidative stress and mitochondrial mass or aging gene expression at cellular level in multiple non-hematopoietic organs. The organ aging in the Atg7-deleted mice was reversed by anatomic connection to wild-type mice with intact blood autophagy via parabiosis, but not by injection of blood cell-free plasma. Our finding thus highlights an essential role of hematopoietic autophagy for decelerating aging in non-hematopoietic organs.

A multicenter study of patients with multisystem Langerhans cell histiocytosis who develop secondary hemophagocytic lymphohistiocytosis.

BACKGROUND: Langerhans cell histiocytosis (LCH) is a rare myeloid neoplasm characterized by the presence of abnormal CD1a-positive (CD1a+ )/CD207+ histiocytes. Hemophagocytic lymphohistiocytosis (HLH) represents a spectrum of hyperinflammatory syndromes typified by the dysregulated activation of the innate and adaptive immune systems. Patients with LCH, particularly those with multisystem (MS) involvement, can develop severe hyperinflammation mimicking that observed in HLH. Nevertheless, to the authors' knowledge, little is known regarding the prevalence, timing, risk factors for development, and outcomes of children and young adults who develop HLH within the context of MS-LCH (hereafter referred to LCH-associated HLH). METHODS: To gain further insights, the authors conducted a retrospective, multicenter study and collected data regarding all patients diagnosed with MS-LCH between 2000 and 2015. RESULTS: Of 384 patients with MS-LCH, 32 were reported by their primary providers to have met the diagnostic criteria for HLH, yielding an estimated 2-year cumulative incidence of 9.3% ± 1.6%. The majority of patients developed HLH at or after the diagnosis of MS-LCH, and nearly one-third (31%) had evidence of an intercurrent infection. Patient age <2 years at the time of diagnosis of LCH; female sex; LCH involvement of the liver, spleen, and hematopoietic system; and a lack of bone involvement each were found to be independently associated with an increased risk of LCH-associated HLH. Patients with MS-LCH who met the criteria for HLH had significantly poorer 5-year survival compared with patients with MS-LCH who did not meet the criteria for HLH (69% vs 97%; P < .0001). CONCLUSIONS: Given its inferior prognosis, further efforts are warranted to enhance the recognition and optimize the treatment of patients with LCH-associated HLH.

PEGylated IL-11 (BBT-059): A Novel Radiation Countermeasure for Hematopoietic Acute Radiation Syndrome.

Interleukin-11 was developed to reduce chemotherapy-induced thrombocytopenia; however, its clinical use was limited by severe adverse effects in humans. PEGylated interleukin-11 (BBT-059), developed by Bolder Biotechnology, Inc., exhibited a longer half-life in rodents and induced longer-lasting increases in hematopoietic cells than interleukin-11. A single dose of 1.2 mg kg of BBT-059, administered subcutaneously to CD2F1 mice (12-14 wk, male) was found to be safe in a 14 d toxicity study. The drug demonstrated its efficacy both as a prophylactic countermeasure and a mitigator in CD2F1 mice exposed to Co gamma total-body irradiation. A single dose of 0.3 mg kg, administered either 24 h pre-, 4 h post-, or 24 h postirradiation increased the survival of mice to 70-100% from lethal doses of radiation. Preadministration (-24 h) of the drug conferred a significantly (p < 0.05) higher survival compared to 24 h post-total-body irradiation. There was significantly accelerated recovery from radiation-induced peripheral blood neutropenia and thrombocytopenia in animals pretreated with BBT-059. The drug also increased bone marrow cellularity and megakaryocytes and accelerated multilineage hematopoietic recovery. In addition, BBT-059 inhibited the induction of radiation-induced hematopoietic biomarkers, thrombopoietin, erythropoietin, and Flt-3 ligand. These results indicate that BBT-059 is a promising radiation countermeasure, demonstrating its potential to be used both pre- and postirradiation for hematopoietic acute radiation syndrome with a broad window for medical management in a radiological or nuclear event.

Low hazard of silver nanoparticles and silver nitrate to the haematopoietic system of rainbow trout.

Silver nanoparticles (Ag NPs) are known for their antibacterial properties and are used in a growing number of nano-enabled products, with inevitable concerns for releases to the environment. Nanoparticles may also be antigenic and toxic to the haematopoietic system, but the immunotoxic effect of Ag NPs on non-target species such as fishes is poorly understood. This study aimed to assess the effect of Ag NP exposure via the water on the haematopoietic system of rainbow trout, Oncorhynchus mykiss, and to determine whether or not the hazard from Ag NPs was different from that of AgNO3. Fish were exposed for 7 days to a control (dechlorinated Plymouth freshwater), dispersant control, 1µgl-1 Ag as AgNO3 or 100µgl-1 Ag NPs. Animals were sampled on days 0, 4 and 7 for haematology, tissue trace metal concentration, biochemistry for evidence of oxidative stress/inflammation in the spleen and histopathology of the blood cells and spleen. The Ag NP treatment significantly increased the haematocrit, but the haematological changes were within the normal physiological range of the animal. Thrombocytes in spleen prints at day 4, and melanomacrophage deposits at day 7 in the spleen, of Ag NP exposed-fish displayed significant increases compared to all the other treatments within the time point. A dialysis experiment confirmed that dissolution rates were very low and any pathology observed is likely from the NP form rather than dissolved metal released from it. Overall, the data showed subtle differences in the effects of Ag NPs compared to AgNO3 on the haematopoietic system. The lack of pathology in the circulating blood cells and melanomacrophage deposits in the spleen suggests a compensatory physiological effort by the spleen to maintain normal circulating haematology during Ag NP exposure.

Treatment Outcome of Children With Multisystem Langerhans Cell Histiocytosis: The Experience of a Single Children's Hospital in Shanghai, China.

We reported the outcome of 150 children newly diagnosed with multisystem langerhans cell histiocytosis following a langerhans cell histiocytosis-II-based protocol (arm B). However, the continuation treatment was extended to 56 weeks and etoposide was omitted from the continuation treatment. Risk organ (RO) involvement was defined as: liver (≥3 cm with or without functional impairment); spleen (≥2 cm below the costal margin in the midclavicular line); hematopoietic system (hemoglobin <100 g/L, and/or white blood cell count <4.0×10/L, and/or platelets <100×10/L). The lungs are not considered a RO in the current study. For the 59 patients with RO involvement (RO+), the rapid response rate (week 6) was 61.0% and the 3-year overall survival 73.4%±5.9%. Rapid responders had a better 3-year survival rate than poor responders (90.9%±5.0% vs. 45.7%±11.0%, P<0.001). Ninety-one patients without RO involvement (RO-) had a relatively low 3-year cumulative reactivation rate (10.7%). No deaths occurred in this subgroup and the 3-year overall survival of RO- patients was 100%. Poor responders of RO+ patients had an extremely poor prognosis. An effective salvage therapy is essential for this high-risk group. The initial treatment intensity and duration of continuation therapy both impact disease reactivation in RO- patients.

Differential effects on gene transcription and hematopoietic differentiation correlate with GATA2 mutant disease phenotypes.

Heterozygous GATA2 mutations underlie an array of complex hematopoietic and lymphatic diseases. Analysis of the literature reporting three recurrent GATA2 germline (g) mutations (gT354M, gR396Q and gR398W) revealed different phenotype tendencies. Although all three mutants differentially predispose to myeloid malignancies, there was no difference in leukemia-free survival for GATA2 patients. Despite intense interest, the molecular pathogenesis of GATA2 mutation is poorly understood. We functionally characterized a GATA2 mutant allelic series representing major disease phenotypes caused by germline and somatic (s) mutations in zinc finger 2 (ZF2). All GATA2 mutants, except for sL359V, displayed reduced DNA-binding affinity and transactivation compared with wild type (WT), which could be attributed to mutations of arginines critical for DNA binding or amino acids required for ZF2 domain structural integrity. Two GATA2 mutants (gT354M and gC373R) bound the key hematopoietic differentiation factor PU.1 more strongly than WT potentially perturbing differentiation via sequestration of PU.1. Unlike WT, all mutants failed to suppress colony formation and some mutants skewed cell fate to granulocytes, consistent with the monocytopenia phenotype seen in GATA2-related immunodeficiency disorders. These findings implicate perturbations of GATA2 function shaping the course of development of myeloid malignancy subtypes and strengthen complete or nearly complete haploinsufficiency for predisposition to lymphedema.

Zymosan-a Protects the Hematopoietic System from Radiation-Induced Damage by Targeting TLR2 Signaling Pathway.

BACKGROUND/AIMS: The hematopoietic system is vulnerable to ionizing radiation and is often severely damaged by radiation. Molecules affecting radioresistance include Toll-like receptor 2. We investigated whether Zymosan-A, a novel TLR2 agonist, can protect the hematopoietic system from radiation-induced damage after total body irradiation. METHODS: Mice were exposed to total body radiation after treatment with Zymosan-A or normal saline, and their survival was recorded. Tissue damage was evaluated by hematoxylin-eosin staining. The number of nucleated cells in bone marrow was determined by flow cytometry. Cell viability and apoptosis assay were determined by CCK-8 assay and flow cytometry assay. Enzyme-linked immunosorbent assay was used to detect the level of cytokines. RESULTS: Zymosan-A protected mice from radiation-induced death and prevented radiation-induced hematopoietic system damage. Zymosan-A also promoted cell viability and inhibited cell apoptosis caused by radiation, induced radioprotective effects via TLR2, upregulated IL-6, IL-11, IL-12, and TNF-α in vivo. CONCLUSION: Zymosan-A can provide protection against radiation-induced hematopoietic system damage by targeting the TLR2 signaling pathway. Thus, Zymosan-A can be potentially effective radioprotectant.

Genome and Epigenome Editing to Treat Disorders of the Hematopoietic System.

The possibility of editing complex genomes in a targeted fashion has revolutionized basic research as well as biomedical and biotechnological applications in the last 5 years. The targeted introduction of genetic changes has allowed researchers to create smart model systems for basic research, bio-engineers to modify crops and farm animals, and translational scientists to develop novel treatment approaches for inherited and acquired disorders for which curative treatment options are not yet available. With the rapid development of genome editing tools, in particular zinc-finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs), and the CRISPR-Cas system, a wide range of therapeutic options have been-and will be-developed at an unprecedented speed, which will change the clinical routine of various disciplines in a revolutionary way. This review summarizes the fundamentals of genome editing and the current state of research. It particularly focuses on the advances made in employing engineered nucleases in hematopoietic stem cells for the treatment of primary immunodeficiencies and hemoglobinopathies, provides a perspective of combining gene editing with the chimeric antigen receptor T cell technology, and concludes by presenting targeted epigenome editing as a novel potential treatment option.