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dc.contributor.authorTarighat, Somayeh S
dc.contributor.authorFei, Fei
dc.contributor.authorJoo, Eun Ji
dc.contributor.authorAbdel-Azim, Hisham
dc.contributor.authorYang, Lu
dc.contributor.authorGeng, Huimin
dc.contributor.authorBum-Erdene, Khuchtumur
dc.contributor.authorGrice, I Darren
dc.contributor.authorvon Itzstein, Mark
dc.contributor.authorBlanchard, Helen
dc.contributor.authorHeisterkamp, Nora
dc.date.accessioned2021-11-17T05:21:45Z
dc.date.available2021-11-17T05:21:45Z
dc.date.issued2021
dc.identifier.issn1422-0067
dc.identifier.doi10.3390/ijms222212167
dc.identifier.urihttp://hdl.handle.net/10072/410182
dc.description.abstractEnvironmentally-mediated drug resistance in B-cell precursor acute lymphoblastic leukemia (BCP-ALL) significantly contributes to relapse. Stromal cells in the bone marrow environment protect leukemia cells by secretion of chemokines as cues for BCP-ALL migration towards, and adhesion to, stroma. Stromal cells and BCP-ALL cells communicate through stromal galectin-3. Here, we investigated the significance of stromal galectin-3 to BCP-ALL cells. We used CRISPR/Cas9 genome editing to ablate galectin-3 in stromal cells and found that galectin-3 is dispensable for steady-state BCP-ALL proliferation and viability. However, efficient leukemia migration and adhesion to stromal cells are significantly dependent on stromal galectin-3. Importantly, the loss of stromal galectin-3 production sensitized BCP-ALL cells to conventional chemotherapy. We therefore tested novel carbohydrate-based small molecule compounds (Cpd14 and Cpd17) with high specificity for galectin-3. Consistent with results obtained using galectin-3-knockout stromal cells, treatment of stromal-BCP-ALL co-cultures inhibited BCP-ALL migration and adhesion. Moreover, these compounds induced anti-leukemic responses in BCP-ALL cells, including a dose-dependent reduction of viability and proliferation, the induction of apoptosis and, importantly, the inhibition of drug resistance. Collectively, these findings indicate galectin-3 regulates BCP-ALL cell responses to chemotherapy through the interactions between leukemia cells and the stroma, and show that a combination of galectin-3 inhibition with conventional drugs can sensitize the leukemia cells to chemotherapy.
dc.description.peerreviewedYes
dc.languageen
dc.publisherMDPI AG
dc.relation.ispartofpagefrom12167
dc.relation.ispartofissue22
dc.relation.ispartofjournalInternational Journal of Molecular Sciences
dc.relation.ispartofvolume22
dc.subject.fieldofresearchGlycobiology
dc.subject.fieldofresearchOncology and carcinogenesis
dc.subject.fieldofresearchClinical sciences
dc.subject.fieldofresearchBiochemistry and cell biology
dc.subject.fieldofresearchMicrobiology
dc.subject.fieldofresearchMedicinal and biomolecular chemistry
dc.subject.fieldofresearchcode310107
dc.subject.fieldofresearchcode3211
dc.subject.fieldofresearchcode3202
dc.subject.fieldofresearchcode3101
dc.subject.fieldofresearchcode3107
dc.subject.fieldofresearchcode3404
dc.titleOvercoming Microenvironment-Mediated Chemoprotection through Stromal Galectin-3 Inhibition in Acute Lymphoblastic Leukemia
dc.typeJournal article
dc.type.descriptionC1 - Articles
dcterms.bibliographicCitationTarighat, SS; Fei, F; Joo, EJ; Abdel-Azim, H; Yang, L; Geng, H; Bum-Erdene, K; Grice, ID; von Itzstein, M; Blanchard, H; Heisterkamp, N, Overcoming Microenvironment-Mediated Chemoprotection through Stromal Galectin-3 Inhibition in Acute Lymphoblastic Leukemia, International Journal of Molecular Sciences, 22 (22), pp. 12167
dcterms.licensehttps://creativecommons.org/licenses/by/4.0/
dc.date.updated2021-11-16T22:14:25Z
dc.description.versionVersion of Record (VoR)
gro.rights.copyright© 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
gro.hasfulltextFull Text
gro.griffith.authorGrice, Darren D.
gro.griffith.authorvon Itzstein, Mark


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