Role of MSC-derived galectin 3 in the AML microenvironment

Abstract

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.

LGALS3 is connected to CD74 in a previously unknown protein network that is associated with poor survival in patients with AML

“…Galectin 3 (LGALS3) is a beta-galactoside binding protein that participates in diverse cellular processes that support cell growth and cell survival [[1], [2], [3], [4], [5], [6], [7], [8], [9]]. There are at least fourteen known galectin family members of which ten are found in mammalian cells [1].…”

“…LGALS3 is the only galectin which can form pentamers and this enables the galectin to form lattices and thus participate in endocytotic processes [1]. LGALS3 is an excellent example of a molecule that acts as a tumor promoter in the context of the entire tumor microenvironment by promoting survival of malignant cells, supporting metastasis, suppressing immune surveillance, and modulating inflammatory expression of chemokines/cytokines [[1], [2], [3], [4], [5], [6], [7], [8], [9]]. LGALS3 supports cell survival by diverse mechanisms.…”

“…LGALS3 regulated pathways are involved in expression of genes and protein associated with cancer stem cells (CSC) and thus the galectin likely supports CSC [9]. Recent data suggests that LGALS3 supports malignant cell survival in AML [6,15,18]. In a cohort of Taiwanese AML patients, Cheng and colleagues reported that elevated LGALS3 mRNA was prognostic for poor survival outcome [18].…”

Galectin-3-Mediated Glial Crosstalk Drives Oligodendrocyte Differentiation and (Re)myelination

“…In the cytoplasm, it plays an anti-apoptotic role, as it interacts with Bcl-2, and it also modulates signaling pathways in order to promote or inhibit cell growth, proliferation and differentiation. It activates Akt ( Kariya et al, 2018 ; Ruvolo et al, 2018 ), inhibits or activates Erk 1/2 ( Alge-Priglinger et al, 2011 ; Mori et al, 2015 ; Zhang et al, 2017 ), and increases β-catenin levels ( Shimura et al, 2004 ; Hu et al, 2015 ), among other functions, depending on the cell types evaluated. In the nucleus, Gal-3 is crucial for pre-mRNA splicing, as it is incorporated into spliceosomes by associating with the U1 small nuclear ribonucleoprotein (snRNP) complex ( Patterson et al, 2002 ; Haudek et al, 2010 ).…”

Upregulation ofAKR1C1in mesenchymal stromal cells promotes the survival of acute myeloid leukaemia cells

“…The abnormal MSCs in the leukaemic BM microenvironment drive the pathogenesis and progression of leukaemia (Corradi et al , ; Yehudai‐Resheff et al , ) by activating multiple pro‐survival pathways in the blasts (Zeng et al , ). Abdul‐Aziz et al () showed that the pro‐survival effect of AML‐MSCs on the AML blasts was mediated by the MIF/PKCβ/IL8 pathway, while Ruvolo et al () identified LGALS3 as a survival factor in the AML cells. Nevertheless, given the complexity of the interactions between MSCs and leukaemia cells, further studies are needed to explore the mechanisms underlying the pro‐leukaemic effects of the abnormal MSCs.…”