Anti-apoptotic ARC protein confers chemoresistance by controlling leukemia-microenvironment interactions through a NFκB/IL1β signaling network

Handle URI:
http://hdl.handle.net/10754/609124
Title:
Anti-apoptotic ARC protein confers chemoresistance by controlling leukemia-microenvironment interactions through a NFκB/IL1β signaling network
Authors:
Carter, Bing Z.; Mak, Po Yee; Chen, Ye; Mak, Duncan H.; Mu, Hong; Jacamo, Rodrigo; Ruvolo, Vivian; Arold, Stefan T. ( 0000-0001-5278-0668 ) ; Ladbury, John E.; Burks, Jared K.; Kornblau, Steven; Andreeff, Michael
Abstract:
To better understand how the apoptosis repressor with caspase recruitment domain (ARC) protein confers drug resistance in acute myeloid leukemia (AML), we investigated the role of ARC in regulating leukemia-mesenchymal stromal cell (MSC) interactions. In addition to the previously reported effect on AML apoptosis, we have demonstrated that ARC enhances migration and adhesion of leukemia cells to MSCs both in vitro and in a novel human extramedullary bone/bone marrow mouse model. Mechanistic studies revealed that ARC induces IL1β expression in AML cells and increases CCL2, CCL4, and CXCL12 expression in MSCs, both through ARC-mediated activation of NFκB. Expression of these chemokines in MSCs increased by AML cells in an ARC/IL1β-dependent manner; likewise, IL1β expression was elevated when leukemia cells were co-cultured with MSCs. Further, cells from AML patients expressed the receptors for and migrated toward CCL2, CCL4, and CXCL12. Inhibition of IL1β suppressed AML cell migration and sensitized the cells co-cultured with MSCs to chemotherapy. Our results suggest the existence of a complex ARC-regulated circuit that maintains intimate connection of AML with the tumor microenvironment through NFκB/IL1β-regulated chemokine receptor/ligand axes and reciprocal crosstalk resulting in cytoprotection. The data implicate ARC as a promising drug target to potentially sensitize AML cells to chemotherapy.
KAUST Department:
Computational Bioscience Research Center (CBRC); Biological and Environmental Sciences and Engineering (BESE) Division
Citation:
Anti-apoptotic ARC protein confers chemoresistance by controlling leukemia-microenvironment interactions through a NFκB/IL1β signaling network 2016 Oncotarget
Publisher:
Impact Journals, LLC
Journal:
Oncotarget
Issue Date:
11-Apr-2016
DOI:
10.18632/oncotarget.7911
Type:
Article
ISSN:
1949-2553
Sponsors:
This work was supported in part by grants from the National Institutes of Health (P01 CA055164 and MD Anderson’s Cancer Center Support Grant CA016672) and the Paul and Mary Haas Chair in Genetics to MA and by the University Cancer Foundation via the Institutional Research Grant program at the University of Texas MD Anderson Cancer Center to BZC. The research by STA reported in this publication was supported by funding from King Abdullah University of Science and Technology (KAUST).
Additional Links:
http://www.oncotarget.com/abstract/7911
Appears in Collections:
Articles; Computational Bioscience Research Center (CBRC); Biological and Environmental Sciences and Engineering (BESE) Division

Full metadata record

DC FieldValue Language
dc.contributor.authorCarter, Bing Z.en
dc.contributor.authorMak, Po Yeeen
dc.contributor.authorChen, Yeen
dc.contributor.authorMak, Duncan H.en
dc.contributor.authorMu, Hongen
dc.contributor.authorJacamo, Rodrigoen
dc.contributor.authorRuvolo, Vivianen
dc.contributor.authorArold, Stefan T.en
dc.contributor.authorLadbury, John E.en
dc.contributor.authorBurks, Jared K.en
dc.contributor.authorKornblau, Stevenen
dc.contributor.authorAndreeff, Michaelen
dc.date.accessioned2016-05-12T07:10:23Zen
dc.date.available2016-05-12T07:10:23Zen
dc.date.issued2016-04-11en
dc.identifier.citationAnti-apoptotic ARC protein confers chemoresistance by controlling leukemia-microenvironment interactions through a NFκB/IL1β signaling network 2016 Oncotargeten
dc.identifier.issn1949-2553en
dc.identifier.doi10.18632/oncotarget.7911en
dc.identifier.urihttp://hdl.handle.net/10754/609124en
dc.description.abstractTo better understand how the apoptosis repressor with caspase recruitment domain (ARC) protein confers drug resistance in acute myeloid leukemia (AML), we investigated the role of ARC in regulating leukemia-mesenchymal stromal cell (MSC) interactions. In addition to the previously reported effect on AML apoptosis, we have demonstrated that ARC enhances migration and adhesion of leukemia cells to MSCs both in vitro and in a novel human extramedullary bone/bone marrow mouse model. Mechanistic studies revealed that ARC induces IL1β expression in AML cells and increases CCL2, CCL4, and CXCL12 expression in MSCs, both through ARC-mediated activation of NFκB. Expression of these chemokines in MSCs increased by AML cells in an ARC/IL1β-dependent manner; likewise, IL1β expression was elevated when leukemia cells were co-cultured with MSCs. Further, cells from AML patients expressed the receptors for and migrated toward CCL2, CCL4, and CXCL12. Inhibition of IL1β suppressed AML cell migration and sensitized the cells co-cultured with MSCs to chemotherapy. Our results suggest the existence of a complex ARC-regulated circuit that maintains intimate connection of AML with the tumor microenvironment through NFκB/IL1β-regulated chemokine receptor/ligand axes and reciprocal crosstalk resulting in cytoprotection. The data implicate ARC as a promising drug target to potentially sensitize AML cells to chemotherapy.en
dc.description.sponsorshipThis work was supported in part by grants from the National Institutes of Health (P01 CA055164 and MD Anderson’s Cancer Center Support Grant CA016672) and the Paul and Mary Haas Chair in Genetics to MA and by the University Cancer Foundation via the Institutional Research Grant program at the University of Texas MD Anderson Cancer Center to BZC. The research by STA reported in this publication was supported by funding from King Abdullah University of Science and Technology (KAUST).en
dc.language.isoenen
dc.publisherImpact Journals, LLCen
dc.relation.urlhttp://www.oncotarget.com/abstract/7911en
dc.rightsArchived with thanks to Oncotarget. All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License. http://creativecommons.org/licenses/by/3.0/en
dc.subjectAMLen
dc.subjectARCen
dc.subjectNFκBen
dc.subjectchemoresistanceen
dc.titleAnti-apoptotic ARC protein confers chemoresistance by controlling leukemia-microenvironment interactions through a NFκB/IL1β signaling networken
dc.typeArticleen
dc.contributor.departmentComputational Bioscience Research Center (CBRC)en
dc.contributor.departmentBiological and Environmental Sciences and Engineering (BESE) Divisionen
dc.identifier.journalOncotargeten
dc.eprint.versionPublisher's Version/PDFen
dc.contributor.institutionSection of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USAen
dc.contributor.institutionDepartment of Biochemistry and Molecular Biology and Center for Biomolecular Structure and Function, The University of Texas MD Anderson Cancer Center, Houston, TX, USAen
dc.contributor.affiliationKing Abdullah University of Science and Technology (KAUST)en
kaust.authorArold, Stefan T.en
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