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

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 preven...

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Autores principales: Parting, Oliver, Langer, Samantha, Kuepper, Maja Kim, Wessling, Caroline, Li, Shaoguang, Braunschweig, Till, Chatain, Nicolas, Maié, Tiago, Costa, Ivan G., Crysandt, Martina, Huber, Michael, Brümmendorf, Tim H., Koschmieder, Steffen, Schemionek, Mirle
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7515845/
https://www.ncbi.nlm.nih.gov/pubmed/32684632
http://dx.doi.org/10.1038/s41375-020-0977-8
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author Parting, Oliver
Langer, Samantha
Kuepper, Maja Kim
Wessling, Caroline
Li, Shaoguang
Braunschweig, Till
Chatain, Nicolas
Maié, Tiago
Costa, Ivan G.
Crysandt, Martina
Huber, Michael
Brümmendorf, Tim H.
Koschmieder, Steffen
Schemionek, Mirle
author_facet Parting, Oliver
Langer, Samantha
Kuepper, Maja Kim
Wessling, Caroline
Li, Shaoguang
Braunschweig, Till
Chatain, Nicolas
Maié, Tiago
Costa, Ivan G.
Crysandt, Martina
Huber, Michael
Brümmendorf, Tim H.
Koschmieder, Steffen
Schemionek, Mirle
author_sort Parting, Oliver
collection PubMed
description 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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spelling pubmed-75158452020-10-07 Therapeutic inhibition of FcγRIIb signaling targets leukemic stem cells in chronic myeloid leukemia Parting, Oliver Langer, Samantha Kuepper, Maja Kim Wessling, Caroline Li, Shaoguang Braunschweig, Till Chatain, Nicolas Maié, Tiago Costa, Ivan G. Crysandt, Martina Huber, Michael Brümmendorf, Tim H. Koschmieder, Steffen Schemionek, Mirle Leukemia Article 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. Nature Publishing Group UK 2020-07-20 2020 /pmc/articles/PMC7515845/ /pubmed/32684632 http://dx.doi.org/10.1038/s41375-020-0977-8 Text en © 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/.
spellingShingle Article
Parting, Oliver
Langer, Samantha
Kuepper, Maja Kim
Wessling, Caroline
Li, Shaoguang
Braunschweig, Till
Chatain, Nicolas
Maié, Tiago
Costa, Ivan G.
Crysandt, Martina
Huber, Michael
Brümmendorf, Tim H.
Koschmieder, Steffen
Schemionek, Mirle
Therapeutic inhibition of FcγRIIb signaling targets leukemic stem cells in chronic myeloid leukemia
title Therapeutic inhibition of FcγRIIb signaling targets leukemic stem cells in chronic myeloid leukemia
title_full Therapeutic inhibition of FcγRIIb signaling targets leukemic stem cells in chronic myeloid leukemia
title_fullStr Therapeutic inhibition of FcγRIIb signaling targets leukemic stem cells in chronic myeloid leukemia
title_full_unstemmed Therapeutic inhibition of FcγRIIb signaling targets leukemic stem cells in chronic myeloid leukemia
title_short Therapeutic inhibition of FcγRIIb signaling targets leukemic stem cells in chronic myeloid leukemia
title_sort therapeutic inhibition of fcγriib signaling targets leukemic stem cells in chronic myeloid leukemia
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7515845/
https://www.ncbi.nlm.nih.gov/pubmed/32684632
http://dx.doi.org/10.1038/s41375-020-0977-8
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