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Τετάρτη 7 Αυγούστου 2019

Neutrophil Progenitors Function as a Mechanistic Link Between Sleep Disruption and Heart Disease
imageNo abstract available
Update – PROFILE: Early-Stage Researchers Advancing Insights on TTP through a Unique PhD Track
imageNo abstract available
Chemo-immunotherapy for Older Patients with Chronic Lymphocytic Leukemia – Passé Yet?
No abstract available
Chemo-immunotherapy for Older Patients with Chronic Lymphocytic Leukemia – Time to Retire?
No abstract available
EHA Guidance Document The process of CAR-T cell therapy in Europe
No abstract available
Chimeric Antigen Receptor T-Cell Therapy Clinical Results in Pediatric and Young Adult B-ALL
imageChimeric antigen receptor (CAR)-modified T-cell therapy has revolutionized the care of patients with relapsed and refractory B-cell acute lymphoblastic leukemia (B-ALL). Results from clinical trials across multiple institutions report remarkable remission rates with CD19-directed CAR-modified T-cell therapy. These remissions are also proving to be durable in many patients with a relapse-free survival (RFS) of approximately 50% to 60% at 1 year across several trials and institutions in this population that has been historically very difficult to treat. In addition, new products are being developed to enhance upon the original CAR T-cell products, which include a humanized CAR, allogeneic CARs, and both CD22 and biallelic CD19 and CD22 constructs. Toxicity after CAR-modified T-cell therapy is characterized by cytokine release syndrome (CRS) and neurotoxicity in the acute post-infusion period and B-cell aplasia as a long-term consequence of treatment. This review will summarize the published data thus far on the use of CAR-modified T-cell therapy in pediatric B-ALL and outline the various CAR products now being developed for this population. Delivery of this therapy and the decision to pursue hematopoietic stem cell transplant (HSCT) after treatment will be discussed.
Transcriptomic and Epigenomic Profiling of Histone Deacetylase Inhibitor Treatment Reveals Distinct Gene Regulation Profiles Leading to Impaired Neutrophil Development
imageThe clinical use of histone deacetylase inhibitors (HDACi) for the treatment of bone marrow failure and hematopoietic malignancies has increased dramatically over the last decades. Nonetheless, their effects on normal myelopoiesis remain poorly evaluated. Here, we treated cord blood derived CD34+ progenitor cells with two chemically distinct HDACi inhibitors MS-275 or SAHA and analyzed their effects on the transcriptome (RNA-seq), epigenome (H3K27ac ChIP-seq) and functional and morphological characteristics during neutrophil development. MS-275 (entinostat) selectively inhibits class I HDACs, with a preference for HDAC1, while SAHA (vorinostat) is a non-selective class I/II HDACi. Treatment with individual HDACi resulted in both overlapping and distinct effects on both transcriptome and epigenome, whereas functional effects were relatively similar. Both HDACi resulted in reduced expansion and increased apoptosis in neutrophil progenitor cells. Morphologically, HDACi disrupted normal neutrophil differentiation what was illustrated by decreased percentages of mature neutrophils. In addition, while SAHA treatment clearly showed a block at the promyelocytic stage, MS-275 treatment was characterized by dysplastic features and skewing towards the monocytic lineage. These effects could be mimicked using shRNA-mediated knockdown of HDAC1. Taken together, our data provide novel insights into the effects of HDAC inhibition on normal hematopoietic cells during neutrophil differentiation. These findings should be taken into account when considering the clinical use of MS-275 and SAHA, and can be potentially utilized to tailor more specific, hematopoietic-directed HDACi in the future.
Anagrelide Modulates Proplatelet Formation Resulting in Decreased Number and Increased Size of Platelets
imageWe retrospectively evaluated 48 essential thrombocythemia (ET) patients who were treated in our institute (male/female, 14/34, median age, 61.5 years). In 14 patients treated with anagrelide (ANA), the degree of platelet count reduction (median, −56.6%) was strongly correlated with increase of mean platelet volume (MPV) (median, +11.7%) (R = 0.777). This correlation was not observed in ET patients treated with hydroxycarbamide alone (R = 0.245). The change in size of platelets strongly suggested that ANA affected the final process of platelet production. Thus, we hypothesized that ANA modifies the process by which platelets are released from proplatelets. To verify the association in an in vitro setting, we compared MEG-01 cells treated with PMA ± ANA. The number of platelet-like particles (PLPs) was decreased (P < 0.05) and the size of PLPs estimated by using flow cytometry was significantly increased when MEG-01 cells were treated with PMA + ANA (P < 0.05 vs PMA alone), recapitulating the clinical findings. The cytoplasmic protrusions extending from MEG-01 cells were shorter and thicker and the number of proplatelets was decreased when MEG-01 cells were treated with PMA + ANA (P < 0.01 vs PMA alone). Western blotting analysis showed that ANA treatment resulted in increased phosphorylation of MLC2 and reduced phosphorylation of focal adhesion kinase (FAK). The morphological change of proplatelets were reversed by blebbistatin, a specific inhibitor of myosin II. These findings indicated that ANA modulates the FAK-RhoA-ROCK-MLC2-myosine IIA pathway and suppresses proplatelet maturation, leading to a decrease in platelet count and increase in MPV.
The Complexity of Genotype-Phenotype Correlations in Hereditary Spherocytosis: A Cohort of 95 Patients: Genotype-Phenotype Correlation in Hereditary Spherocytosis
imageHereditary spherocytosis (HS) is a phenotypically and genetically heterogeneous disease. With the increased use of Next Generation Sequencing (NGS) techniques in the diagnosis of red blood cell disorders, the list of unique pathogenic mutations underlying HS is growing rapidly. In this study, we aimed to explore genotype-phenotype correlation in 95 HS patients genotyped by targeted NGS as part of routine diagnostics (UMC Utrecht, Utrecht, The Netherlands). In 85/95 (89%) of patients a pathogenic mutation was identified, including 56 novel mutations. SPTA1 mutations were most frequently encountered (36%, 31/85 patients), primarily in patients with autosomal recessive forms of HS. Three SPTA1 (α-spectrin) mutations showed autosomal dominant inheritance. ANK1 (ankyrin1) mutations accounted for 27% (23/85 patients) and SPTB (β-spectrin) mutations for 20% (17/85 patients). Moderate or severe HS was more frequent in patients with SPTB or ANK1 mutations, reflected by lower hemoglobin concentrations and higher reticulocyte counts. Interestingly, mutations affecting spectrin association domains of ANK1, SPTA1 and SPTB resulted in more severe phenotypes. Additionally, we observed a clear association between phenotype and aspects of red cell deformability as determined by the Laser assisted Optical Rotational Cell Analyzer (LoRRca MaxSis). Both maximal deformability and area under the curve were negatively associated with disease severity (respectively r = −0.46, p < 0.01, and r = −0.39, p = 0.01). Genotype-phenotype prediction in HS facilitates insight in consequences of pathogenic mutations for the assembly and dynamic interactions of the red cell cytoskeleton. In addition, we show that measurements of red blood cell deformability are clearly correlated with HS severity.
Attenuated Acceleration to Leukemia after Ezh2 Loss in Nup98-HoxD13 (NHD13) Myelodysplastic Syndrome
imageNo abstract available

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