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Exposure of Patient-Derived Mesenchymal Stromal Cells To Author Manuscript Published OnlineFirst on July 8, 2020; DOI: 10.1158/1541-7786.MCR-20-0091 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 1 Research Article 2 Exposure of patient-derived mesenchymal stromal cells to TGFB1 supports fibrosis 3 induction in a pediatric acute megakaryoblastic leukemia model 4 Theresa Hack1, Stefanie Bertram2, Helen Blair3, Verena Börger4, Guntram Büsche5, Lora 5 Denson1, Enrico Fruth1, Bernd Giebel4, Olaf Heidenreich3,6, Ludger Klein-Hitpass7, 6 Laxmikanth Kollipara8, Stephanie Sendker1, Albert Sickmann8,9,10, Christiane Walter1, Nils 7 von Neuhoff1, Helmut Hanenberg1,11, Dirk Reinhardt1, Markus Schneider1,* and Mareike 8 Rasche1,* 9 1 Department of Pediatric Hematology and Oncology, University Children’s Hospital Essen, 10 Essen, Germany 11 2 Department of Pathology, University Hospital Essen, Essen, Germany 12 3 Newcastle University, Wolfson Childhood Cancer Research Centre, Translation and Clinical 13 Research Institute, Newcastle upon Tyne, United Kingdom 14 4 Institute for Transfusion Medicine, University Hospital Essen, Essen, Germany 15 5 Department of Pathology, Hannover Medical School, Hannover, Germany 16 6 Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands 17 7 Department of Cell Biology, University Hospital Essen, Essen, Germany 18 8 Leibniz-Institut für Analytische Wissenschaften – ISAS – e.V., Dortmund, Germany 19 9 Department of Chemistry, College of Physical Sciences, University of Aberdeen, Aberdeen, 20 Scotland, United Kingdom 21 10 Medizinische Fakultät, Medizinische Proteom-Center (MPC), Ruhr-Universität Bochum, 22 Bochum, Germany 23 11 Department of Otorhinolaryngology and Head/Neck Surgery, Heinrich Heine University, 24 Düsseldorf, Germany 25 * These authors contributed equally to this work. 26 Keywords: leukemic bone marrow niche, myeloid leukemia in children with Down 27 syndrome (ML-DS), acute megakaryoblastic leukemia (AMKL), TGFB1, bone marrow 28 fibrosis 29 Running title: TGFB1 supports fibrosis in pediatric AMKL 30 Funding: G.B. was supported by the Cluster of Excellence “Rebirth, humanized animal 31 models”, funded by the Deutsche Forschungsgemeinschaft, Germany. T.H. was funded by 32 the Boehringer Ingelheim Fonds with a travel grant. D.R. was funded by the Essener 33 Elterninitiative zur Unterstützung krebskranker Kinder e.V.. S.S. was funded by the 34 Essener Ausbildungsprogramm "Labor und Wissenschaft" für den aerztlichen Nachwuchs. 35 Correspondence to: Markus Schneider, Department of Pediatric Hematology and 36 Oncology, University Children’s Hospital Essen, 45147 Essen, Germany, email: 37 [email protected], phone: +49-201-723-1056, fax: +49-201-723-5591; Downloaded from mcr.aacrjournals.org on October 1, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on July 8, 2020; DOI: 10.1158/1541-7786.MCR-20-0091 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 38 Mareike Rasche, Department of Pediatric Hematology and Oncology, University Children’s 39 Hospital Essen, 45147 Essen, Germany, email: [email protected], phone: 40 +49-201-723-1051, fax: +49-201-723-5591 41 Conflicts of Interest: The authors declare no conflict of interest regarding this study. The 42 funders had no role in the design of the study; in the collection, analyses, or interpretation 43 of data; in the writing of the manuscript, or in the decision to publish the results. 44 Abstract counts: 241 45 Word counts: 5004 46 Number of figures and tables: 5 47 2 Downloaded from mcr.aacrjournals.org on October 1, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on July 8, 2020; DOI: 10.1158/1541-7786.MCR-20-0091 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 48 Abstract: Bone marrow fibrosis (BMF) is a rare complication in acute leukemia. In 49 pediatrics, it predominantly occurs in acute megakaryoblastic leukemia (AMKL) and here 50 especially in patients with trisomy 21, called myeloid leukemia in Down syndrome (ML- 51 DS). Defects in mesenchymal stromal cells (MSCs) and cytokines specifically released by 52 the myeloid blasts are thought to be the main drivers of fibrosis in the bone marrow niche 53 (BMN). In order to model the BMN of pediatric AMKL patients in mice, we first established 54 MSCs from pediatric patients with AMKL (n=5) and ML-DS (n=9). Healthy donor (HD) 55 control MSCs (n=6) were generated from unaffected children and adolescents ≤18 years 56 of age. Steady-state analyses of the MSCs revealed that patient-derived MSCs exhibited 57 decreased adipogenic differentiation potential and enrichment of proliferation-associated 58 genes. Importantly, TGFB1 exposure in vitro promoted early profibrotic changes in all three 59 MSC entities. To study BMF induction for longer periods of time, we created an in vivo 60 humanized artificial BMN subcutaneously in immunodeficient NSG mice, using a mixture of 61 MSCs, HUVECs and Matrigel. Injection of AMKL blasts as producers of TGFB1 into this 62 BMN after eight weeks induced fibrosis grade I/II in a dose-dependent fashion over a time 63 period of four weeks. Thus, our study developed a humanized mouse model that will be 64 instrumental to specifically examine leukemogenesis and therapeutic targets for AMKL 65 blasts in future. 66 Implications: TGFB1 supports fibrosis induction in a pediatric acute megakaryoblastic 67 leukemia model generated with patient-derived mesenchymal stromal cells. 68 Introduction 69 Acute megakaryoblastic leukemia (AMKL) is diagnosed in approximately 10% of 70 pediatric acute myeloid leukemia (AML) patients [1]. Here, AMKL occurs in two different 71 settings: myeloid leukemia in children with Down syndrome (ML-DS) and also in patients 72 with euploid genomes [1-3]. ML-DS is preceded by a transient abnormal myelopoiesis 73 (TAM) in infants, accompanied by GATA1s mutation in blasts and liver fibrosis. Despite 74 excellent event-free and overall survival, patients with ML-DS still have an increased risk of 75 severe chemotherapy-associated complications [2-5]. In contrast, pediatric AMKL in 76 patients without DS is a heterogeneous disease and usually arises in children until the age 77 of three years with mostly poor outcome [1]. 78 The physiological bone marrow niche (BMN) is a complex network consisting of 79 extracellular matrix (ECM) proteins, non-hematopoietic cells as well as soluble factors. 80 Mesenchymal stromal cells (MSCs) as multipotent progenitor cells are important members 81 of the BMN, which contribute to these physiological functions and can differentiate into 82 other cells in the BMN such as osteoblasts and adipocytes [6]. However, in context of 83 myeloid disorders such as AMKL [1, 7], myeloproliferative neoplasm (MPN), hairy cell 3 Downloaded from mcr.aacrjournals.org on October 1, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on July 8, 2020; DOI: 10.1158/1541-7786.MCR-20-0091 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 84 leukemia and myelodysplastic syndrome [8], MSCs are key for the pathological changes 85 that occur, as they can transform to contractile myofibroblast with high α-smooth muscle 86 actin (αSMA) expression, extensive secretion of ECM proteins and increased stromal 87 fibers [9, 10]. These changes ultimately lead to bone marrow fibrosis (BMF), which 88 histologically is defined by decreased or absent adipocytes [11], an increase in bone 89 marrow stromal fibers [10] and in late stage occurrence of osteosclerosis [12]. As most 90 disorders with increased bone marrow stromal fibers are associated with abnormalities of 91 the number or function of megakaryocytes [10], it is not surprising that the histological 92 pictures of AMKL in adults with consecutive development of BMF is indistinguishable to the 93 changes observed in the BMN in the pediatric AMKL patients with and without trisomy 21 94 [7]. 95 A major factor for the pathological changes that occur in the leukemic BMN in AMKL 96 are increased concentrations of TGFB1, which is predominantly secreted by 97 megakaryocytes and platelets [13] and also AMKL blasts [8, 14]. TGFB1 is one of the 98 strongest inducer of collagen synthesis and considered as key driver of BMF [13, 15, 16]. 99 Several reports support the profibrotic role of TGFB1 in AMKL [17, 18], but it remains 100 unclear whether the secretion of TGFB1 from leukemic megakaryoblasts may be sufficient 101 to induce the BMF by itself, leading to a self-reinforcing leukemic BMN, or if additional 102 factors such as pathological changes in non-hematopoietic cells e.g. MSCs are essential 103 prerequisite for in the induction of BMF [19, 20]. 104 We therefore decided to use our unique resources in pediatric leukemia to address the 105 question whether specific changes in the MSCs derived from children and adolescents 106 with AMKL (with or without trisomy 21) exist that are necessary for the BMF observed in 107 pediatric and also adult AMKL or whether the simple overexpression of TGFB1 by AMKL 108 blasts is already sufficient for the BMF to occur. To this end, we analyzed MSCs derived 109 from pediatric AMKL with (ML-DS) or without Down syndrome or from healthy donors 110 (HDs) ≤18 years in vitro under different conditions or in vivo by generating a humanized 111 artificial BMN in immunodeficient mice. We further tested which pathological changes can 112 be induced in the humanized BMN in vivo by TGFB1. 113 Elucidating the interactions between leukemic blasts and the MSCs derived from 114 AMKL patients without or with Morbus Down in an in vitro or in vivo model systems will 115 ultimately be instrumental to identify potentially druggable target genes to improve the 116 outcome of not just AMKL but also other hematological conditions with BMF. 117 Materials and Methods 118 Cell lines, patients and healthy donor samples 4 Downloaded from mcr.aacrjournals.org on October 1, 2021.
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