UMMS Affiliation

Department of Medicine

Publication Date

2020-10-01

Document Type

Article

Disciplines

Cancer Biology | Hemic and Lymphatic Diseases | Neoplasms | Oncology

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 (FcgammaRIIb, CD32b) for being critical in LSC resistance and show that targeting FcgammaRIIb downstream signaling, by using a Food and Drug Administration-approved BTK inhibitor, provides a successful therapeutic approach. First, we identified FcgammaRIIb upregulation in primary CML stem cells. FcgammaRIIb depletion caused reduced serial re-plaiting efficiency and cell proliferation in malignant cells. FcgammaRIIb 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-FcgammaRIIb-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.

Keywords

Cancer stem cells, Haematological cancer

Rights and Permissions

Copyright © The Author(s) 2020. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

DOI of Published Version

10.1038/s41375-020-0977-8

Source

Parting O, Langer S, Kuepper MK, Wessling C, Li S, Braunschweig T, Chatain N, Maié T, Costa IG, Crysandt M, Huber M, Brümmendorf TH, Koschmieder S, Schemionek M. Therapeutic inhibition of FcγRIIb signaling targets leukemic stem cells in chronic myeloid leukemia. Leukemia. 2020 Oct;34(10):2635-2647. doi: 10.1038/s41375-020-0977-8. Epub 2020 Jul 20. PMID: 32684632; PMCID: PMC7515845. Link to article on publisher's site

Journal/Book/Conference Title

Leukemia

Related Resources

Link to Article in PubMed

PubMed ID

32684632

Creative Commons License

Creative Commons Attribution 4.0 License
This work is licensed under a Creative Commons Attribution 4.0 License.

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