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Thoas Fioretos

Thoas Fioretos

Research team manager

Thoas Fioretos

Arrayed molecular barcoding identifies TNFSF13 as a positive regulator of acute myeloid leukemia-initiating cells

Author

  • Marion Chapellier
  • Pablo Peña-Martínez
  • Ramprasad Ramakrishnan
  • Mia Eriksson
  • Mehrnaz Safaee-Talkhoncheh
  • Christina Orsmark-Pietras
  • Henrik Lilljebjörn
  • Carl Högberg
  • Anna Hagström-Andersson
  • Thoas Fioretos
  • Jonas Larsson
  • Marcus Järås
Show all

Summary, in English

Dysregulation of cytokines in the bone marrow microenvironment promotes acute myeloid leukemia cell growth. Due to the complexity and low throughput of in vivo stem-cell based assays, studying the role of cytokines in the bone marrow niche in a screening setting is challenging. Herein, we developed an ex vivo cytokine screen using 11 arrayed molecular barcodes, allowing for a competitive in vivo readout of leukemia-initiating capacity. With this approach, we assessed the effect of 114 murine cytokines on MLL-AF9 acute myeloid leukemia mouse cells and identified the tumor necrosis factor ligand superfamily member 13 (TNFSF13) as a positive regulator of leukemia-initiating cells. By using Tnfsf13-/- recipient mice, we confirmed that TNFSF13 supports leukemia-initiation also under physiological conditions. TNFSF13 was secreted by normal myeloid cells but not by leukemia mouse cells, suggesting that mature myeloid bone marrow cells support leukemia cells by secreting TNFSF13. TNFSF13 supported leukemia cell proliferation in an NF-κB-dependent manner by binding TNFRSF17 and suppressed apoptosis. Moreover, TNFSF13 supported the growth and survival of several human myeloid leukemia cell lines, demonstrating that our findings translate to human disease. Taken together, using arrayed molecular barcoding, we identified a previously unrecognized role of TNFSF13 as a positive regulator of acute myeloid leukemia-initiating cells. The arrayed barcoded screening methodology is not limited to cytokines and leukemia, but can be extended to other types of ex vivo screens, where a multiplexed in vivo read-out of stem cell functionality is needed.

Department/s

  • Targeted therapies in leukemia
  • BioCARE: Biomarkers in Cancer Medicine improving Health Care, Education and Innovation
  • Division of Clinical Genetics
  • The pathogenetic mechanisms behind MLL-rearranged acute leukemia in infancy
  • StemTherapy: National Initiative on Stem Cells for Regenerative Therapy
  • Division of Molecular Medicine and Gene Therapy
  • Translational Genomic and Functional Studies of Leukemia

Publishing year

2019

Language

English

Pages

2006-2016

Publication/Series

Haematologica

Volume

104

Issue

10

Document type

Journal article

Publisher

Ferrata Storti Foundation

Topic

  • Cell and Molecular Biology
  • Hematology

Status

Published

Research group

  • Targeted therapies in leukemia
  • The pathogenetic mechanisms behind MLL-rearranged acute leukemia in infancy
  • Translational Genomic and Functional Studies of Leukemia

ISBN/ISSN/Other

  • ISSN: 1592-8721