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Therapeutic inhibition of FcγRIIb signaling targets leukemic stem cells in chronic myeloid leukemia.

Authors
  • Parting, Oliver1
  • Langer, Samantha2
  • Kuepper, Maja Kim1
  • Wessling, Caroline3
  • Li, Shaoguang4
  • Braunschweig, Till5
  • Chatain, Nicolas1
  • Maié, Tiago6
  • Costa, Ivan G6
  • Crysandt, Martina1
  • Huber, Michael7
  • Brümmendorf, Tim H1
  • Koschmieder, Steffen1
  • Schemionek, Mirle8
  • 1 Department of Hematology, Oncology, Hemostaseology, and Stem Cell Transplantation, Faculty of Medicine, University Hospital RWTH Aachen, Aachen, Germany. , (Germany)
  • 2 Department of Transfusion Medicine, University Hospital Essen, Essen, Germany. , (Germany)
  • 3 Department of Neurosurgery, Clemens Hospital, Muenster, Germany. , (Germany)
  • 4 Department of Medicine, University of Massachusetts Medical School, Worcester, MA, USA.
  • 5 Department of Pathology, University Hospital RWTH Aachen, Aachen, Germany. , (Germany)
  • 6 Institute for Computational Genomics, Joint Research Center for Computational Biomedicine, RWTH Aachen University, Aachen, Germany. , (Germany)
  • 7 Institute of Biochemistry and Molecular Immunology, RWTH Aachen University, Aachen, Germany. , (Germany)
  • 8 Department of Hematology, Oncology, Hemostaseology, and Stem Cell Transplantation, Faculty of Medicine, University Hospital RWTH Aachen, Aachen, Germany. [email protected] , (Germany)
Type
Published Article
Journal
Leukemia
Publisher
Springer Nature
Publication Date
Oct 01, 2020
Volume
34
Issue
10
Pages
2635–2647
Identifiers
DOI: 10.1038/s41375-020-0977-8
PMID: 32684632
Source
Medline
Language
English
License
Unknown

Abstract

Despite the successes achieved with molecular targeted inhibition of the oncogenic driver Bcr-Abl in chronic myeloid leukemia (CML), the majority of patients still require lifelong tyrosine kinase inhibitor (TKI) therapy. This is primarily caused by resisting leukemic stem cells (LSCs), which prevent achievement of treatment-free remission in all patients. Here we describe the ITIM (immunoreceptor tyrosine-based inhibition motif)-containing Fc gamma receptor IIb (FcγRIIb, CD32b) for being critical in LSC resistance and show that targeting FcγRIIb downstream signaling, by using a Food and Drug Administration-approved BTK inhibitor, provides a successful therapeutic approach. First, we identified FcγRIIb upregulation in primary CML stem cells. FcγRIIb depletion caused reduced serial re-plaiting efficiency and cell proliferation in malignant cells. FcγRIIb targeting in both a transgenic and retroviral CML mouse model provided in vivo evidence for successful LSC reduction. Subsequently, we identified BTK as a main downstream mediator and targeting the Bcr-Abl-FcγRIIb-BTK axis in primary CML CD34+ cells using ibrutinib, in combination with standard TKI therapy, significantly increased apoptosis in quiescent CML stem cells thereby contributing to the eradication of LSCs.. As a potential curative therapeutic approach, we therefore suggest combining Bcr-Abl TKI therapy along with BTK inhibition.

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