Exposure of Patient-Derived Mesenchymal Stromal Cells to TGFB1 Supports Fibrosis Induction in a Pediatric Acute Megakaryoblastic Leukemia Model

Theresa Hack, Stefanie Bertram, Helen Blair, Verena Börger, Guntram Büsche, Lora Denson, Enrico Fruth, Bernd Giebel, Olaf Heidenreich, Ludger Klein-Hitpass, Laxmikanth Kollipara, Stephanie Sendker, Albert Sickmann, Christiane Walter, Nils von Neuhoff, Helmut Hanenberg, Dirk Reinhardt, Markus Schneider, Mareike Rasche

Research output: Contribution to journalArticlepeer-review

Abstract

Bone marrow fibrosis (BMF) is a rare complication in acute leukemia. In pediatrics, it predominantly occurs in acute megakaryoblastic leukemia (AMKL) and especially in patients with trisomy 21, called myeloid leukemia in Down syndrome (ML-DS). Defects in mesenchymal stromal cells (MSC) and cytokines specifically released by the myeloid blasts are thought to be the main drivers of fibrosis in the bone marrow niche (BMN). To model the BMN of pediatric patients with AMKL in mice, we first established MSCs from pediatric patients with AMKL (n = 5) and ML-DS (n = 9). Healthy donor control MSCs (n = 6) were generated from unaffected children and adolescents ≤18 years of age. Steady-state analyses of the MSCs revealed that patient-derived MSCs exhibited decreased adipogenic differentiation potential and enrichment of proliferation-associated genes. Importantly, TGFB1 exposure in vitro promoted early profibrotic changes in all three MSC entities. To study BMF induction for longer periods of time, we created an in vivo humanized artificial BMN subcutaneously in immunodeficient NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ mice, using a mixture of MSCs, human umbilical vein endothelial cell, and Matrigel. Injection of AMKL blasts as producers of TGFB1 into this BMN after 8 weeks induced fibrosis grade I/II in a dose-dependent fashion over a time period of 4 weeks. Thus, our study developed a humanized mouse model that will be instrumental to specifically examine leukemogenesis and therapeutic targets for AMKL blasts in future. IMPLICATIONS: TGFB1 supports fibrosis induction in a pediatric AMKL model generated with patient-derived MSCs. VISUAL OVERVIEW: http://mcr.aacrjournals.org/content/molcanres/18/10/1603/F1.large.jpg.

Original languageEnglish
Pages (from-to)1603-1612
Number of pages10
JournalMolecular cancer research : MCR
Volume18
Issue number10
DOIs
Publication statusPublished - Oct 2020
Externally publishedYes

Keywords

  • Animals
  • Disease Models, Animal
  • Fibrosis
  • Humans
  • Immunophenotyping/methods
  • Leukemia, Megakaryoblastic, Acute
  • Male
  • Mesenchymal Stem Cells/metabolism
  • Mice
  • Transforming Growth Factor beta1/metabolism

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