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Cooperating, congenital neutropenia-associated Csf3r and Runx1 mutations activate pro-inflammatory signaling and inhibit myeloid differentiation of mouse HSPCs.

Authors
  • Ritter, Malte1
  • Klimiankou, Maksim1
  • Klimenkova, Olga1
  • Schambach, Axel2, 3
  • Hoffmann, Dirk2
  • Schmidt, Amy4
  • Kanz, Lothar1
  • Link, Daniel C4
  • Welte, Karl5
  • Skokowa, Julia6
  • 1 Division of Translational Oncology, Department of Hematology, Oncology, Clinical Immunology and Rheumatology, University Hospital Tübingen, Otfried-Müller-Straße 10, 72076, Tübingen, Germany. , (Germany)
  • 2 Institute of Experimental Hematology, Hannover Medical School, Hannover, Germany. , (Germany)
  • 3 Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
  • 4 Division of Oncology, Section of Stem Cell Biology, Washington University Medical School, St. Louis, MO, USA.
  • 5 The University Children's Hospital Tübingen, Tübingen, Germany. , (Germany)
  • 6 Division of Translational Oncology, Department of Hematology, Oncology, Clinical Immunology and Rheumatology, University Hospital Tübingen, Otfried-Müller-Straße 10, 72076, Tübingen, Germany. [email protected] , (Germany)
Type
Published Article
Journal
Annals of Hematology
Publisher
Springer-Verlag
Publication Date
Oct 01, 2020
Volume
99
Issue
10
Pages
2329–2338
Identifiers
DOI: 10.1007/s00277-020-04194-0
PMID: 32821971
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Patients with the pre-leukemia bone marrow failure syndrome called severe congenital neutropenia (CN) have an approximately 15% risk of developing acute myeloid leukemia (AML; called here CN/AML). Most CN/AML patients co-acquire CSF3R and RUNX1 mutations, which play cooperative roles in the development of AML. To establish an in vitro model of leukemogenesis, we utilized bone marrow lin- cells from transgenic C57BL/6-d715 Csf3r mice expressing a CN patient-mimicking truncated CSF3R mutation. We transduced these cells with vectors encoding RUNX1 wild type (WT) or RUNX1 mutant proteins carrying the R139G or R174L mutations. Cells transduced with these RUNX1 mutants showed diminished in vitro myeloid differentiation and elevated replating capacity, compared with those expressing WT RUNX1. mRNA expression analysis showed that cells transduced with the RUNX1 mutants exhibited hyperactivation of inflammatory signaling and innate immunity pathways, including IL-6, TLR, NF-kappaB, IFN, and TREM1 signaling. These data suggest that the expression of mutated RUNX1 in a CSF3R-mutated background may activate the pro-inflammatory cell state and inhibit myeloid differentiation.

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