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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 (Fc\u03b3RIIb, CD32b) for being critical in LSC resistance and show that targeting Fc\u03b3RIIb downstream signaling, by using a Food and Drug Administration-approved BTK inhibitor, provides a successful therapeutic approach. First, we identified Fc\u03b3RIIb upregulation in primary CML stem cells. Fc\u03b3RIIb depletion caused reduced serial re-plaiting efficiency and cell proliferation in malignant cells. Fc\u03b3RIIb 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-Fc\u03b3RIIb-BTK axis in primary CML CD34<jats:sup>+<\/jats:sup>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.<\/jats:p>","DOI":"10.1038\/s41375-020-0977-8","type":"journal-article","created":{"date-parts":[[2020,7,20]],"date-time":"2020-07-20T01:02:18Z","timestamp":1595206938000},"page":"2635-2647","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Therapeutic inhibition of Fc\u03b3RIIb signaling targets leukemic stem cells in chronic myeloid leukemia"],"prefix":"10.1038","volume":"34","author":[{"given":"Oliver","family":"Parting","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samantha","family":"Langer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maja Kim","family":"Kuepper","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caroline","family":"Wessling","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaoguang","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Till","family":"Braunschweig","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4485-3120","authenticated-orcid":false,"given":"Nicolas","family":"Chatain","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tiago","family":"Mai\u00e9","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2890-8697","authenticated-orcid":false,"given":"Ivan G.","family":"Costa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martina","family":"Crysandt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7222-8686","authenticated-orcid":false,"given":"Michael","family":"Huber","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9677-3723","authenticated-orcid":false,"given":"Tim H.","family":"Br\u00fcmmendorf","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1011-8171","authenticated-orcid":false,"given":"Steffen","family":"Koschmieder","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5947-3529","authenticated-orcid":false,"given":"Mirle","family":"Schemionek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,7,20]]},"reference":[{"key":"977_CR1","doi-asserted-by":"crossref","first-page":"726","DOI":"10.1182\/blood.V86.2.726.bloodjournal862726","volume":"86","author":"T Skorski","year":"1995","unstructured":"Skorski T, Kanakaraj P, Nieborowska-Skorska M, Ratajczak MZ, Wen SC, Zon G, et al. 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All the other authors declare that they have no conflict interest.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}}]}}