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

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          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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          Discontinuation of imatinib in patients with chronic myeloid leukaemia who have maintained complete molecular remission for at least 2 years: the prospective, multicentre Stop Imatinib (STIM) trial.

          Imatinib treatment significantly improves survival in patients with chronic myeloid leukaemia (CML), but little is known about whether treatment can safely be discontinued in the long term. We aimed to assess whether imatinib can be discontinued without occurrence of molecular relapse in patients in complete molecular remission (CMR) while on imatinib. In our prospective, multicentre, non-randomised Stop Imatinib (STIM) study, imatinib treatment (of >2 years duration) was discontinued in patients with CML who were aged 18 years and older and in CMR (>5-log reduction in BCR-ABL and ABL levels and undetectable transcripts on quantitative RT-PCR). Patients who had undergone immunomodulatory treatment (apart from interferon α), treatment for other malignancies, or allogeneic haemopoietic stem-cell transplantation were not included. Patients were enrolled at 19 participating institutions in France. In this interim analysis, rate of relapse was assessed by use of RT-PCR for patients with at least 12 months of follow-up. Imatinib was reintroduced in patients who had molecular relapse. This study is registered with ClinicalTrials.gov, number NCT00478985. 100 patients were enrolled between July 9, 2007, and Dec 17, 2009. Median follow-up was 17 months (range 1-30), and 69 patients had at least 12 months follow-up (median 24 months, range 13-30). 42 (61%) of these 69 patients relapsed (40 before 6 months, one patient at month 7, and one at month 19). At 12 months, the probability of persistent CMR for these 69 patients was 41% (95% CI 29-52). All patients who relapsed responded to reintroduction of imatinib: 16 of the 42 patients who relapsed showed decreases in their BCR-ABL levels, and 26 achieved CMR that was sustained after imatinib rechallenge. Imatinib can be safely discontinued in patients with a CMR of at least 2 years duration. Imatinib discontinuation in this setting yields promising results for molecular relapse-free survival, raising the possibility that, at least in some patients, CML might be cured with tyrosine kinase inhibitors. Copyright © 2010 Elsevier Ltd. All rights reserved.
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            Human chronic myeloid leukemia stem cells are insensitive to imatinib despite inhibition of BCR-ABL activity.

            Imatinib therapy, which targets the oncogene product BCR-ABL, has transformed chronic myeloid leukemia (CML) from a life-threatening disease into a chronic condition. Most patients, however, harbor residual leukemia cells, and disease recurrence usually occurs when imatinib is discontinued. Although various mechanisms to explain leukemia cell persistence have been proposed, the critical question from a therapeutic standpoint--whether disease persistence is BCR-ABL dependent or independent--has not been answered. Here, we report that human CML stem cells do not depend on BCR-ABL activity for survival and are thus not eliminated by imatinib therapy. Imatinib inhibited BCR-ABL activity to the same degree in all stem (CD34+CD38-, CD133+) and progenitor (CD34+CD38+) cells and in quiescent and cycling progenitors from newly diagnosed CML patients. Although short-term in vitro imatinib treatment reduced the expansion of CML stem/progenitors, cytokine support permitted growth and survival in the absence of BCR-ABL activity that was comparable to that of normal stem/progenitor counterparts. Our findings suggest that primitive CML cells are not oncogene addicted and that therapies that biochemically target BCR-ABL will not eliminate CML stem cells.
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              Immune inhibitory receptors.

              With the detailed description and analysis of several inhibitory receptor systems on lymphoid and myeloid cells, a central paradigm has emerged in which the pairing of activation and inhibition is necessary to initiate, amplify, and then terminate immune responses. In some cases, the activating and inhibitory receptors recognize similar ligands, and the net outcome is determined by the relative strength of these opposing signals. The importance of this modulation is demonstrated by the sometimes fatal autoimmune disorders observed in mice with targeted disruption of inhibitory receptors. The significance of these receptors is further evidenced by the conservation of immunoreceptor tyrosine-based inhibitory motifs during their evolution.
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                Author and article information

                Contributors
                mschemionek@ukaachen.de
                Journal
                Leukemia
                Leukemia
                Leukemia
                Nature Publishing Group UK (London )
                0887-6924
                1476-5551
                20 July 2020
                20 July 2020
                2020
                : 34
                : 10
                : 2635-2647
                Affiliations
                [1 ]GRID grid.412301.5, ISNI 0000 0000 8653 1507, Department of Hematology, Oncology, Hemostaseology, and Stem Cell Transplantation, Faculty of Medicine, , University Hospital RWTH Aachen, ; Aachen, Germany
                [2 ]GRID grid.410718.b, ISNI 0000 0001 0262 7331, Department of Transfusion Medicine, , University Hospital Essen, ; Essen, Germany
                [3 ]Department of Neurosurgery, Clemens Hospital, Muenster, Germany
                [4 ]GRID grid.168645.8, ISNI 0000 0001 0742 0364, Department of Medicine, , University of Massachusetts Medical School, ; Worcester, MA USA
                [5 ]GRID grid.412301.5, ISNI 0000 0000 8653 1507, Department of Pathology, , University Hospital RWTH Aachen, ; Aachen, Germany
                [6 ]GRID grid.1957.a, ISNI 0000 0001 0728 696X, Institute for Computational Genomics, Joint Research Center for Computational Biomedicine, , RWTH Aachen University, ; Aachen, Germany
                [7 ]GRID grid.1957.a, ISNI 0000 0001 0728 696X, Institute of Biochemistry and Molecular Immunology, , RWTH Aachen University, ; Aachen, Germany
                Author information
                http://orcid.org/0000-0003-4485-3120
                http://orcid.org/0000-0003-2890-8697
                http://orcid.org/0000-0001-7222-8686
                http://orcid.org/0000-0002-9677-3723
                http://orcid.org/0000-0002-1011-8171
                http://orcid.org/0000-0002-5947-3529
                Article
                977
                10.1038/s41375-020-0977-8
                7515845
                32684632
                758ac898-3c2e-4d2a-ac09-22b506b10b25
                © 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/.

                History
                : 16 March 2020
                : 2 July 2020
                : 7 July 2020
                Funding
                Funded by: FundRef https://doi.org/10.13039/501100001659, Deutsche Forschungsgemeinschaft (German Research Foundation);
                Award ID: SCHE 1938/1-1
                Award Recipient :
                Categories
                Article
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                © Springer Nature Limited 2020

                Oncology & Radiotherapy
                cancer stem cells,haematological cancer
                Oncology & Radiotherapy
                cancer stem cells, haematological cancer

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