TY - JOUR
T1 - Role of MSC-derived galectin 3 in the AML microenvironment
AU - Ruvolo, Peter P.
AU - Ruvolo, Vivian R.
AU - Burks, Jared K.
AU - Qiu, Yi Hua
AU - Wang, Rui Yu
AU - Shpall, Elizabeth J.
AU - Mirandola, Leonardo
AU - Hail, Numsen
AU - Zeng, Zhihong
AU - McQueen, Teresa
AU - Daver, Naval
AU - Post, Sean M.
AU - Chiriva-Internati, Maurizio
AU - Kornblau, Steven M.
AU - Andreeff, Michael
N1 - Publisher Copyright:
© 2018 Elsevier B.V.
PY - 2018/7
Y1 - 2018/7
N2 - In acute myeloid leukemia (AML), high Galectin 3 (LGALS3) expression is associated with poor prognosis. The role of LGALS3 derived from mesenchymal stromal cells (MSC) in the AML microenvironment is unclear; however, we have recently found high LGALS3 expression in MSC derived from AML patients is associated with relapse. In this study, we used reverse phase protein analysis (RPPA) to correlate LGALS3 expression in AML MSC with 119 other proteins including variants of these proteins such as phosphorylated forms or cleaved forms to identify biologically relevant pathways. RPPA revealed that LGALS3 protein was positively correlated with expression of thirteen proteins including MYC, phosphorylated beta-Catenin (p-CTNNB1), and AKT2 and negatively correlated with expression of six proteins including integrin beta 3 (ITGB3). String analysis revealed that proteins positively correlated with LGALS3 showed strong interconnectivity. Consistent with the RPPA results, LGALS3 suppression by shRNA in MSC resulted in decreased MYC and AKT expression while ITGB3 was induced. In co-culture, the ability of AML cell to adhere to MSC LGALS3 shRNA transductants was reduced compared to AML cell adhesion to MSC control shRNA transductants. Finally, use of novel specific LGALS3 inhibitor CBP.001 in co-culture of AML cells with MSC reduced viable leukemia cell populations with induced apoptosis and augmented the chemotherapeutic effect of AraC. In summary, the current study demonstrates that MSC-derived LGALS3 may be critical for important biological pathways for MSC homeostasis and for regulating AML cell localization and survival in the leukemia microenvironmental niche.
AB - In acute myeloid leukemia (AML), high Galectin 3 (LGALS3) expression is associated with poor prognosis. The role of LGALS3 derived from mesenchymal stromal cells (MSC) in the AML microenvironment is unclear; however, we have recently found high LGALS3 expression in MSC derived from AML patients is associated with relapse. In this study, we used reverse phase protein analysis (RPPA) to correlate LGALS3 expression in AML MSC with 119 other proteins including variants of these proteins such as phosphorylated forms or cleaved forms to identify biologically relevant pathways. RPPA revealed that LGALS3 protein was positively correlated with expression of thirteen proteins including MYC, phosphorylated beta-Catenin (p-CTNNB1), and AKT2 and negatively correlated with expression of six proteins including integrin beta 3 (ITGB3). String analysis revealed that proteins positively correlated with LGALS3 showed strong interconnectivity. Consistent with the RPPA results, LGALS3 suppression by shRNA in MSC resulted in decreased MYC and AKT expression while ITGB3 was induced. In co-culture, the ability of AML cell to adhere to MSC LGALS3 shRNA transductants was reduced compared to AML cell adhesion to MSC control shRNA transductants. Finally, use of novel specific LGALS3 inhibitor CBP.001 in co-culture of AML cells with MSC reduced viable leukemia cell populations with induced apoptosis and augmented the chemotherapeutic effect of AraC. In summary, the current study demonstrates that MSC-derived LGALS3 may be critical for important biological pathways for MSC homeostasis and for regulating AML cell localization and survival in the leukemia microenvironmental niche.
KW - Acute myeloid leukemia
KW - Galectin 3
KW - Integrin beta 3
KW - MYC
KW - Reverse phase protein analysis
KW - Tumor microenvironment
UR - http://www.scopus.com/inward/record.url?scp=85045576939&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85045576939&partnerID=8YFLogxK
U2 - 10.1016/j.bbamcr.2018.04.005
DO - 10.1016/j.bbamcr.2018.04.005
M3 - Article
C2 - 29655803
AN - SCOPUS:85045576939
SN - 0167-4889
VL - 1865
SP - 959
EP - 969
JO - Biochimica et Biophysica Acta - Molecular Cell Research
JF - Biochimica et Biophysica Acta - Molecular Cell Research
IS - 7
ER -