dc.contributor.author | Tarighat, Somayeh S | |
dc.contributor.author | Fei, Fei | |
dc.contributor.author | Joo, Eun Ji | |
dc.contributor.author | Abdel-Azim, Hisham | |
dc.contributor.author | Yang, Lu | |
dc.contributor.author | Geng, Huimin | |
dc.contributor.author | Bum-Erdene, Khuchtumur | |
dc.contributor.author | Grice, I Darren | |
dc.contributor.author | von Itzstein, Mark | |
dc.contributor.author | Blanchard, Helen | |
dc.contributor.author | Heisterkamp, Nora | |
dc.date.accessioned | 2021-11-17T05:21:45Z | |
dc.date.available | 2021-11-17T05:21:45Z | |
dc.date.issued | 2021 | |
dc.identifier.issn | 1422-0067 | |
dc.identifier.doi | 10.3390/ijms222212167 | |
dc.identifier.uri | http://hdl.handle.net/10072/410182 | |
dc.description.abstract | Environmentally-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.peerreviewed | Yes | |
dc.language | en | |
dc.publisher | MDPI AG | |
dc.relation.ispartofpagefrom | 12167 | |
dc.relation.ispartofissue | 22 | |
dc.relation.ispartofjournal | International Journal of Molecular Sciences | |
dc.relation.ispartofvolume | 22 | |
dc.subject.fieldofresearch | Glycobiology | |
dc.subject.fieldofresearch | Oncology and carcinogenesis | |
dc.subject.fieldofresearch | Clinical sciences | |
dc.subject.fieldofresearch | Biochemistry and cell biology | |
dc.subject.fieldofresearch | Microbiology | |
dc.subject.fieldofresearch | Medicinal and biomolecular chemistry | |
dc.subject.fieldofresearchcode | 310107 | |
dc.subject.fieldofresearchcode | 3211 | |
dc.subject.fieldofresearchcode | 3202 | |
dc.subject.fieldofresearchcode | 3101 | |
dc.subject.fieldofresearchcode | 3107 | |
dc.subject.fieldofresearchcode | 3404 | |
dc.title | Overcoming Microenvironment-Mediated Chemoprotection through Stromal Galectin-3 Inhibition in Acute Lymphoblastic Leukemia | |
dc.type | Journal article | |
dc.type.description | C1 - Articles | |
dcterms.bibliographicCitation | Tarighat, 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.license | https://creativecommons.org/licenses/by/4.0/ | |
dc.date.updated | 2021-11-16T22:14:25Z | |
dc.description.version | Version 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.hasfulltext | Full Text | |
gro.griffith.author | Grice, Darren D. | |
gro.griffith.author | von Itzstein, Mark | |