TY - JOUR A1 - Maucher, Marius A1 - Srour, Micha A1 - Danhof, Sophia A1 - Einsele, Hermann A1 - Hudecek, Michael A1 - Yakoub-Agha, Ibrahim T1 - Current limitations and perspectives of chimeric antigen receptor-T-cells in acute myeloid leukemia JF - Cancers N2 - Adoptive transfer of gene-engineered chimeric antigen receptor (CAR)-T-cells has emerged as a powerful immunotherapy for combating hematologic cancers. Several target antigens that are prevalently expressed on AML cells have undergone evaluation in preclinical CAR-T-cell testing. Attributes of an ‘ideal’ target antigen for CAR-T-cell therapy in AML include high-level expression on leukemic blasts and leukemic stem cells (LSCs), and absence on healthy tissues, normal hematopoietic stem and progenitor cells (HSPCs). In contrast to other blood cancer types, where CAR-T therapies are being similarly studied, only a rather small number of AML patients has received CAR-T-cell treatment in clinical trials, resulting in limited clinical experience for this therapeutic approach in AML. For curative AML treatment, abrogation of bulk blasts and LSCs is mandatory with the need for hematopoietic recovery after CAR-T administration. Herein, we provide a critical review of the current pipeline of candidate target antigens and corresponding CAR-T-cell products in AML, assess challenges for clinical translation and implementation in routine clinical practice, as well as perspectives for overcoming them. KW - AML KW - CAR-T-cell KW - hematology KW - gene therapy KW - adoptive cell therapy Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-252180 SN - 2072-6694 VL - 13 IS - 24 ER - TY - JOUR A1 - Laukner, Anna A1 - Truchet, Laura A1 - Manukjan, Georgi A1 - Schulze, Harald A1 - Langbein-Detsch, Ines A1 - Mueller, Elisabeth A1 - Leeb, Tosso A1 - Kehl, Alexandra T1 - Effects of cocoa genotypes on coat color, platelets and coagulation parameters in French Bulldogs JF - Genes N2 - A nonsense variant in HPS3, c.2420G>A or p.Trp807*, was recently discovered as the cause for a brown coat color termed cocoa in French Bulldogs. Here, we studied the genotype–phenotype correlation regarding coat color in HPS3 mutant dogs that carried various combinations of mutant alleles at other coat color genes. Different combinations of HPS3, MLPH and TYRP1 genotypes resulted in subtly different shades of brown coat colors. As HPS3 variants in humans cause the Hermansky–Pudlak syndrome type 3, which in addition to oculocutaneous albinism is characterized by a storage pool deficiency leading to bleeding tendency, we also investigated the phenotypic consequences of the HPS3 variant in French Bulldogs on hematological parameters. HPS3 mutant dogs had a significantly lowered platelet dense granules abundance. However, no increased bleeding tendencies in daily routine were reported by dog owners. We therefore conclude that in dogs, the phenotypic effect of the HPS3 variant is largely restricted to pigmentation. While an effect on platelet morphology is evident, we did not obtain any indications for major health problems associated with the cocoa coat color in French Bulldogs. Further studies will be necessary to definitely rule out very subtle effects on visual acuity or a clinically relevant bleeding disorder. KW - Canis lupus familiaris KW - dog KW - thrombocyte KW - pigmentation KW - hematology KW - platelet Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-242745 SN - 2073-4425 VL - 12 IS - 7 ER - TY - JOUR A1 - Manukjan, Georgi A1 - Wiegering, Verena A1 - Reindl, Tobias A1 - Strauß, Gabriele A1 - Klopocki, Eva A1 - Schulze, Harald A1 - Andres, Oliver T1 - Novel variants in FERMT3 and RASGRP2 - Genetic linkage in Glanzmann-like bleeding disorders JF - Pediatric Blood & Cancer N2 - Defects of platelet intracellular signaling can result in severe platelet dysfunction. Several mutations in each of the linked genes FERMT3 and RASGRP2 on chromosome 11 causing a Glanzmann‐like bleeding phenotype have been identified so far. We report on novel variants in two unrelated pediatric patients with severe bleeding diathesis—one with leukocyte adhesion deficiency type III due to a homozygous frameshift in FERMT3 and the other with homozygous variants in both, FERMT3 and RASGRP2 . We focus on the challenging genetic and functional variant assessment and aim to accentuate the risk of obtaining misleading results due to the phenomenon of genetic linkage. KW - bleding disorders other than hemophilia KW - hematology KW - hemostasis and thrombosis KW - platelet disorders Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-208129 VL - 67 IS - 2 ER - TY - JOUR A1 - Waaga, AM A1 - Krzymanski, M. A1 - Ulrichs, Karin A1 - Wierusz-Wysocka, Bogna A1 - Müller-Buchholtz, Wolfgang T1 - Hematological effects of the new immunosuppressive drug 15-deoxyspergualin N2 - Since systematic hematological studies on blood and bone marrow changes after treatment with 15-Deoxyspergualin (DOS) are lacking, a quantitative assessment was performed fourteen or twenty eight days after intraperitoneal application of DOS to rats. Further observations done 7 and 14 days after discontinuation of DOS administration allowed analysis of banc marrow regeneration. DOS induced lymphocytopenia, granUlocytopenia and anemia with a decrease of bone marrow cellularity due to suppression of cell maturation. The effect was dose-dependent and bone marrow as well as blood changes were observed in animals treated with doses from 0.5 to 10.0 mg/kg DOS. Within 14 days after termination of the treatment, rapid recovery with normalization of all hematological parameters was observed. In the light of our data, these hematological side effects may not be a major disadvantage, if DOS is used in doses below 2.5 mg/kg, and for a course of therapy which is limited to 7 to 14 days. KW - Chirurgie KW - 15-Deoxyspergualin KW - hematology KW - immunosuppression KW - bone marrow KW - regeneration KW - experimental therapy Y1 - 1993 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-44701 ER -