Cohesin mutation dysregulates erythropoiesis and granulopoiesis output within the whole kidney marrow of adult zebrafish.

Cohesin complex is essential for cell division and regulating cell type-specific gene expression programs. Mutations in genes encoding the cohesin subunits are associated with hematological malignancies, preleukemia, and clonal hematopoiesis of indeterminate potential. In this study, we examined how cohesin mutation impacts hematopoiesis using adult zebrafish that carry heterozygous germline nonsense mutation in the cohesin subunit, () that is orthologous to human .

Megakaryocyte maturation involves activation of the adaptive unfolded protein response.

Endoplasmic reticulum stress triggers the unfolded protein response (UPR) to promote cell survival or apoptosis. Transient endoplasmic reticulum stress activation has been reported to trigger megakaryocyte production, and UPR activation has been reported as a feature of megakaryocytic cancers. However, the role of UPR signaling in megakaryocyte biology is not fully understood.

Insights into the role of JAK2-I724T variant in myeloproliferative neoplasms from a unique cohort of New Zealand patients.

Objectives: This study aimed to compile bioinformatic and experimental information for missense variants previously reported in myeloproliferative neoplasms (MPN) and determine if germline -I724T, recently found to be common in New Zealand Polynesians, associates with MPN.

Methods: For all variants found in the literature, gnomAD_exome allele frequencies were extracted and REVEL scores were calculated using the dbNSFP database. We investigated the prevalence of -I724T in a cohort of 111 New Zealand MPN patients using a TaqMan assay, examined its allelic co-occurrence with -V617F using Oxford Nanopore sequencing, and modelled the impact of I724T on JAK2 using I-Mutant and ChimeraX software.

Advances in molecular characterization of pediatric acute megakaryoblastic leukemia not associated with Down syndrome; impact on therapy development.

Acute megakaryoblastic leukemia (AMKL) is a rare subtype of acute myeloid leukemia (AML) in which leukemic blasts have megakaryocytic features. AMKL makes up 4%-15% of newly diagnosed pediatric AML, typically affecting young children (less than 2 years old). AMKL associated with Down syndrome (DS) shows mutations and has a favorable prognosis.

N-methyl-D-aspartate receptor regulates the circadian clock in megakaryocytic cells and impacts cell proliferation through BMAL1.

Peripheral circadian clocks control cell proliferation and survival, but little is known about their role and regulation in megakaryocytic cells. N-methyl-D-aspartate receptor (NMDAR) regulates the central clock in the brain. The purpose of this study was to determine whether NMDAR regulates the megakaryocytic cell clock and whether the megakaryocytic clock regulates cell proliferation and cell death.

Endoplasmic reticulum protein 5 attenuates platelet endoplasmic reticulum stress and secretion in a mouse model.

Extracellular protein disulfide isomerases (PDIs), including PDI, endoplasmic reticulum protein 57 (ERp57), ERp72, ERp46, and ERp5, are required for in vivo thrombus formation in mice. Platelets secrete PDIs upon activation, which regulate platelet aggregation. However, platelets secrete only ∼10% of their PDI content extracellularly.

Deregulated calcium signaling in blood cancer: Underlying mechanisms and therapeutic potential.

Intracellular calcium signaling regulates diverse physiological and pathological processes. In solid tumors, changes to calcium channels and effectors mutations or changes in expression affect all cancer hallmarks. Such changes often disrupt transport of calcium ions (Ca) in the endoplasmic reticulum (ER) or mitochondria, impacting apoptosis.

Advances in molecular characterization of myeloid proliferations associated with Down syndrome.

Myeloid leukemia associated with Down syndrome (ML-DS) has a unique molecular landscape that differs from other subtypes of acute myeloid leukemia. ML-DS is often preceded by a myeloproliferative neoplastic condition called transient abnormal myelopoiesis (TAM) that disrupts megakaryocytic and erythroid differentiation. Over the last two decades, many genetic and epigenetic changes in TAM and ML-DS have been elucidated.

Deletion of Grin1 in mouse megakaryocytes reveals NMDA receptor role in platelet function and proplatelet formation.

The process of proplatelet formation (PPF) requires coordinated interaction between megakaryocytes (MKs) and the extracellular matrix (ECM), followed by a dynamic reorganization of the actin and microtubule cytoskeleton. Localized fluxes of intracellular calcium ions (Ca2+) facilitate MK-ECM interaction and PPF. Glutamate-gated N-methyl-D-aspartate receptor (NMDAR) is highly permeable to Ca2+.

The Epidemiology of Myeloproliferative Neoplasms in New Zealand between 2010 and 2017: Insights from the New Zealand Cancer Registry.

Background: There is a paucity of data on ethnic disparities in patients with the classical Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs): polycythaemia vera (PV), essential thrombocythaemia (ET) and primary myelofibrosis (PMF).

Methods: This study analysed the demographic data for PV, ET and PMF collected by the New Zealand Cancer Registry (NZCR) between 2010 and 2017.

Results: We found that the NZCR capture rates were lower than average international incidence rates for PV and ET, but higher for PMF (0.

Ethnic differences in acute promyelocytic leukaemia between New Zealand Polynesian and European patients.

Ethnic differences in haematologic malignancies remain poorly elucidated, hence research in this area is important. This was a retrospective study into potential ethnic disparity in the presentation and outcomes of acute promyelocytic leukaemia (APL) between New Zealand (NZ) Polynesian and European patients. Data were analysed for patients treated at Auckland City Hospital (ACH;  = 55) and recorded in the New Zealand Cancer Registry (NZCR;  = 173), both for the period 2000-2017.

Ionotropic glutamate receptors in platelets: opposing effects and a unifying hypothesis.

Ionotropic glutamate receptors include -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPAR), kainate receptors (KAR), and -methyl-D-aspartate receptors (NMDAR). All function as cation channels; AMPAR and KAR are more permeable to sodium and NMDAR to calcium ions. Compared to the brain, receptor assemblies in platelets are unusual, suggesting distinctive functionalities.

Platelet-Reactive Antibodies in Patients after Ischaemic Stroke-An Epiphenomenon or a Natural Protective Mechanism.

Ischaemic brain damage induces autoimmune responses, including the production of autoantibodies with potential neuroprotective effects. Platelets share unexplained similarities with neurons, and the formation of anti-platelet antibodies has been documented in neurological disorders. The aim of this study was to investigate the presence of anti-platelet antibodies in the peripheral blood of patients after ischaemic stroke and determine any clinical correlations.

-Methyl-D-Aspartate Receptors in Hematopoietic Cells: What Have We Learned?

The -methyl-D-aspartate receptor (NMDAR) provides a pathway for glutamate-mediated inter-cellular communication, best known for its role in the brain but with multiple examples of functionality in non-neuronal cells. Data previously published by others and us provided evidence that NMDARs regulate platelet and red blood cell (RBC) production. Here, we summarize what is known about these hematopoietic roles of the NMDAR.

N-Methyl-D-Aspartate Receptor Hypofunction in Meg-01 Cells Reveals a Role for Intracellular Calcium Homeostasis in Balancing Megakaryocytic-Erythroid Differentiation.

The release of calcium ions (Ca) from the endoplasmic reticulum (ER) and related store-operated calcium entry (SOCE) regulate maturation of normal megakaryocytes. The -methyl-D-aspartate (NMDA) receptor (NMDAR) provides an additional mechanism for Ca influx in megakaryocytic cells, but its role remains unclear. We created a model of NMDAR hypofunction in Meg-01 cells using CRISPR-Cas9 mediated knockout of the gene, which encodes an obligate, GluN1 subunit of the NMDAR.

Early treatment of acute promyelocytic leukaemia is accurately guided by the PML protein localisation pattern: real-life experience from a tertiary New Zealand centre.

Current guidelines recommend that a rapid test be used to assist diagnosis of acute promyelocytic leukaemia (APL), but the choice of an assay is discretionary. PML immunofluorescence (PML IF) identifies the microparticulate pattern of the PML protein localisation, highly specific for APL. The aim of this study was to evaluate clinical utility of PML IF in a real-life setting based on a retrospective records review for all patients who had PML IF performed in our centre between 2000 and 2017.

Distinctive features of polycythaemia vera in New Zealand Polynesians.

Aim: The aim of this study was to examine a potential ethnic disparity in the phenotype of polycythaemia vera (PV) between New Zealand European and Polynesian patients.

Method: A retrospective review of medical records was conducted at Middlemore Hospital to identify adult patients with PV diagnosed between 1987 and 2007. Data extracted included diagnostic criteria, ethnicity, age, complications and survival.

-methyl-d-aspartate receptor mediated calcium influx supports in vitro differentiation of normal mouse megakaryocytes but proliferation of leukemic cell lines.

Background: -methyl-d-aspartate receptors (NMDARs) contribute calcium influx in megakaryocytic cells but their roles remain unclear; both pro- and anti-differentiating effects have been shown in different contexts.

Objectives: The aim of this study was to clarify NMDAR contribution to megakaryocytic differentiation in both normal and leukemic cells.

Methods: Meg-01, Set-2, and K-562 leukemic cell lines were differentiated using phorbol-12-myristate-13-acetate (PMA, 10 nmol L) or valproic acid (VPA, 500 μmol L).

Inhibition of NMDA receptor function with an anti-GluN1-S2 antibody impairs human platelet function and thrombosis.

GluN1 is a mandatory component of N-methyl-D-aspartate receptors (NMDARs) best known for their roles in the brain, but with increasing evidence for relevance in peripheral tissues, including platelets. Certain anti-GluN1 antibodies reduce brain infarcts in rodent models of ischaemic stroke. There is also evidence that human anti-GluN1 autoantibodies reduce neuronal damage in stroke patients, but the underlying mechanism is unclear.

Selected GRIN2A mutations in melanoma cause oncogenic effects that can be modulated by extracellular glutamate.

GRIN2A mutations are frequent in melanoma tumours but their role in disease is not well understood. GRIN2A encodes a modulatory subunit of the N-methyl-d-aspartate receptor (NMDAR). We hypothesized that certain GRIN2A mutations increase NMDAR function and support melanoma growth through oncogenic effects.

Inhibition of glutamate regulated calcium entry into leukemic megakaryoblasts reduces cell proliferation and supports differentiation.

Human megakaryocytes release glutamate and express glutamate-gated Ca(2+)-permeable N-methyl-D-aspartate receptors (NMDARs) that support megakaryocytic maturation. While deregulated glutamate pathways impact oncogenicity in some cancers, the role of glutamate and NMDARs in megakaryocytic malignancies remains unknown. The aim of this study was to determine if NMDARs participate in Ca(2+) responses in leukemic megakaryoblasts and if so, whether modulating NMDAR activity could influence cell growth.

N-methyl-D-aspartate receptors amplify activation and aggregation of human platelets.

Background: Glutamate is stored in platelet dense granules and large amounts (>400 μM) are released during thrombus formation. N-methyl-d-aspartate glutamate receptors (NMDARs) have been shown in platelets but their roles are unclear.

Materials And Methods: Platelet activation indices (CD62P expression and PAC-1 binding) and platelet aggregation were tested in the presence of well-characterized agonists (glutamate, NMDA, glycine) and antagonists (MK-801, memantine, AP5) of neuronal NMDARs.

Evidence That GRIN2A Mutations in Melanoma Correlate with Decreased Survival.

Previous whole-exome sequencing has demonstrated that melanoma tumors harbor mutations in the GRIN2A gene. GRIN2A encodes the regulatory GluN2A subunit of the glutamate-gated N-methyl-d-aspartate receptor (NMDAR), involvement of which in melanoma remains undefined. Here, we sequenced coding exons of GRIN2A in 19 low-passage melanoma cell lines derived from patients with metastatic melanoma.

Stroke patients develop antibodies that react with components of N-methyl-D-aspartate receptor subunit 1 in proportion to lesion size.

Background And Purpose: Antibodies against neuronal antigens develop in patients after stroke and some may serve as biomarkers of neuronal injury. We aimed to determine whether antibodies against subunit 1 (GluN1) of the N-methyl-D-aspartate receptor also develop after stroke and if so, whether they correlate with stroke characteristics.

Methods: Forty-eight patients with ischemic stroke and 96 healthy controls were tested for the presence of serum antibodies targeting GluN1.