Overcoming Microenvironment-Mediated Chemoprotection through Stromal Galectin-3 Inhibition in Acute Lymphoblastic Leukemia

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. Str...

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Autores principales:	Somayeh S. Tarighat, Fei Fei, Eun Ji Joo, Hisham Abdel-Azim, Lu Yang, Huimin Geng, Khuchtumur Bum-Erdene, I. Darren Grice, Mark von Itzstein, Helen Blanchard, Nora Heisterkamp
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	B-cell precursor ALL galectin-3 <i>lgals3</i> galectin microenvironment adhesion Biology (General) QH301-705.5 Chemistry QD1-999
Acceso en línea:	https://doaj.org/article/88e52965b3874a80b7709ddfe968bb2e
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spelling	oai:doaj.org-article:88e52965b3874a80b7709ddfe968bb2e2021-11-25T17:53:57ZOvercoming Microenvironment-Mediated Chemoprotection through Stromal Galectin-3 Inhibition in Acute Lymphoblastic Leukemia10.3390/ijms2222121671422-00671661-6596https://doaj.org/article/88e52965b3874a80b7709ddfe968bb2e2021-11-01T00:00:00Zhttps://www.mdpi.com/1422-0067/22/22/12167https://doaj.org/toc/1661-6596https://doaj.org/toc/1422-0067Environmentally-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.Somayeh S. TarighatFei FeiEun Ji JooHisham Abdel-AzimLu YangHuimin GengKhuchtumur Bum-ErdeneI. Darren GriceMark von ItzsteinHelen BlanchardNora HeisterkampMDPI AGarticleB-cell precursor ALLgalectin-3<i>lgals3</i>galectinmicroenvironmentadhesionBiology (General)QH301-705.5ChemistryQD1-999ENInternational Journal of Molecular Sciences, Vol 22, Iss 12167, p 12167 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	B-cell precursor ALL galectin-3 <i>lgals3</i> galectin microenvironment adhesion Biology (General) QH301-705.5 Chemistry QD1-999
spellingShingle	B-cell precursor ALL galectin-3 <i>lgals3</i> galectin microenvironment adhesion Biology (General) QH301-705.5 Chemistry QD1-999 Somayeh S. Tarighat Fei Fei Eun Ji Joo Hisham Abdel-Azim Lu Yang Huimin Geng Khuchtumur Bum-Erdene I. Darren Grice Mark von Itzstein Helen Blanchard Nora Heisterkamp Overcoming Microenvironment-Mediated Chemoprotection through Stromal Galectin-3 Inhibition in Acute Lymphoblastic Leukemia
description	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.
format	article
author	Somayeh S. Tarighat Fei Fei Eun Ji Joo Hisham Abdel-Azim Lu Yang Huimin Geng Khuchtumur Bum-Erdene I. Darren Grice Mark von Itzstein Helen Blanchard Nora Heisterkamp
author_facet	Somayeh S. Tarighat Fei Fei Eun Ji Joo Hisham Abdel-Azim Lu Yang Huimin Geng Khuchtumur Bum-Erdene I. Darren Grice Mark von Itzstein Helen Blanchard Nora Heisterkamp
author_sort	Somayeh S. Tarighat
title	Overcoming Microenvironment-Mediated Chemoprotection through Stromal Galectin-3 Inhibition in Acute Lymphoblastic Leukemia
title_short	Overcoming Microenvironment-Mediated Chemoprotection through Stromal Galectin-3 Inhibition in Acute Lymphoblastic Leukemia
title_full	Overcoming Microenvironment-Mediated Chemoprotection through Stromal Galectin-3 Inhibition in Acute Lymphoblastic Leukemia
title_fullStr	Overcoming Microenvironment-Mediated Chemoprotection through Stromal Galectin-3 Inhibition in Acute Lymphoblastic Leukemia
title_full_unstemmed	Overcoming Microenvironment-Mediated Chemoprotection through Stromal Galectin-3 Inhibition in Acute Lymphoblastic Leukemia
title_sort	overcoming microenvironment-mediated chemoprotection through stromal galectin-3 inhibition in acute lymphoblastic leukemia
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/88e52965b3874a80b7709ddfe968bb2e
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Overcoming Microenvironment-Mediated Chemoprotection through Stromal Galectin-3 Inhibition in Acute Lymphoblastic Leukemia

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