Aberrantly expressed LGR4 empowers Wnt signaling in multiple myeloma by hijacking osteoblast-derived R-spondins

Andel, Harmen van; Ren, Zhen; Koopmans, Iris; Joosten, Sander P.J.; Kocemba, Kinga A.; Lau, Wim de; Kersten, Marie José; Bruin, Alexander M. de; Guikema, Jeroen E. J.; Spaargaren, Marcel; Pals, Steven T.

doi:10.1073/pnas.1618650114

Cited by 37 publications

(45 citation statements)

References 63 publications

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“…It has been reported that LGR4, 5, and 6 are strong potentiators of Wnt/β‐catenin signaling . Several studies have highlighted the crucial role of LGR4 in the promotion of osteoblast differentiation by activating the Wnt signaling pathway . Intriguingly, in the present study, BMP9 had no effect on the expression level of the LGR4 gene but dramatically augmented the expression of the LGR6 gene.…”

Section: Discussioncontrasting

confidence: 56%

BMP9 Reduces Bone Loss in Ovariectomized Mice by Dual Regulation of Bone Remodeling

Zhou

Yang

Jing

et al. 2020

Journal of Bone and Mineral Research

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Bone remodeling is dynamic and is tightly regulated through bone resorption dominated by osteoclasts and bone formation dominated by osteoblasts. Imbalances in this process can cause various pathological conditions, such as osteoporosis. Bone morphogenetic protein 9 (BMP9), a biomolecule produced and secreted by the liver, has many pharmacological effects, including anti-liver fibrosis, antitumor, anti-heart failure, and antidiabetic activities. However, the effects of BMP9 on the regulation of osteoblast and osteoclast functions and the underlying molecular mechanism(s) have not yet been investigated. In this study, BMP9 increased the expression of osteoblastogenic gene markers, such as ALP, Cola1, OCN, RUNX2, and OSX, and ALP activity in MC3T3-E1 cells by upregulating LGR6 and activating the Wnt/β-catenin pathway. BMP9 also suppressed receptor activator of nuclear factor-κB (NF-κB) ligand (RANKL)-induced osteoclast differentiation of bone marrow macrophages (BMMs) by inhibiting the Akt-NF-κB-NFATc1 pathway. More importantly, in an ovariectomy (OVX) mouse model, BMP9 attenuated bone loss and improved bone biomechanical properties in vivo by increasing bone-forming activity and suppressing bone resorption activity. Accordingly, our current work highlights the dual regulatory effects that BMP9 exerts on bone remodeling by promoting bone anabolic activity and inhibiting osteoclast differentiation in OVX mice.

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Section: Discussioncontrasting

confidence: 56%

BMP9 Reduces Bone Loss in Ovariectomized Mice by Dual Regulation of Bone Remodeling

Zhou

Yang

Jing

et al. 2020

Journal of Bone and Mineral Research

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“…Instead, oncogenic Wnt pathway activity in MM involves autocrine and/or paracrine Wnt ligands 19,21,32,33 and is potentiated by aberrant expression and turnover of Wnt (co)receptors and transcriptional activators, as well as by loss of negative Wnt pathway regulators. These activating events include aberrant expression of the R-spondin receptor LGR4 34 and of the transcriptional coactivator BCL9, 35,36 epigenetic silencing of the feedback inhibitors secreted Fzd-related proteins and DKK1, 21,33 and mutational inactivation of CYLD, a deubiquinating enzyme that negatively regulates Wnt. 37 Given the ligand dependence of Wnt pathway activation in MM, targeting of Wnt receptors and coreceptors, disconnecting the MM cells from their growth-promoting microenvironment, is a potentially promising therapeutic strategy for MM.…”

Section: Introductionmentioning

confidence: 99%

Syndecan-1 promotes Wnt/β-catenin signaling in multiple myeloma by presenting Wnts and R-spondins

Ren

Andel

Lau

et al. 2018

Blood

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Multiple myeloma (MM) is characterized by the expansion of malignant plasma cells in the bone marrow (BM). Most MMs display aberrant Wnt/β-catenin signaling, which drives proliferation; however, they lack oncogenic Wnt pathway mutations, suggesting activation by autocrine Wnt ligands and/or paracrine Wnts from the BM microenvironment. Expression of the heparan sulfate (HS) proteoglycan syndecan-1 is a hallmark of MM. Syndecan-1 is a critical player in the complex reciprocal interaction between MM cells and their BM niche, mediating growth factor/cytokine binding and signaling by its HS chains. Here, by means of CRISPR/Cas9-mediated knockout and doxycycline-inducible short hairpin RNA-mediated knockdown of EXT1, a critical enzyme for HS polymerization, we demonstrate that the HS chains decorating syndecan-1 mediate aberrant Wnt pathway activation in MM. HS-deficient MM cells exhibited strongly decreased autocrine Wnt/β-catenin pathway activity and reduced Wnt pathway-dependent proliferation. In addition, we demonstrate that Wnts bind to the HS side chains of syndecan-1 and that this binding contributes to paracrine Wnt pathway activation through the Wnt receptor Frizzled (Fzd). Furthermore, in an HS-dependent fashion, syndecan-1 also binds osteoblast-produced R-spondin, which represses Fzd degradation by activation of LGR4, an R-spondin receptor aberrantly expressed on MM cells. Costimulation with R-spondin and its binding to HS chains decorating syndecan-1 are indispensable for optimal stimulation of Wnt signaling in MM. Taken together, our results identify syndecan-1 as a crucial component of the Wnt signalosome in MM cells, binding Wnts and R-spondins to promote aberrant Wnt/β-catenin signaling and cell growth, and suggest HS and its biosynthetic enzymes as potential targets in the treatment of MM.

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“…The CML-BC cell line KBM5 and the imatinibresistant KBM5-T315I subclone were kind gifts from Dr. Carter and Dr. Andreeff (MD Anderson Cancer Center, Houston, TX). The multiple myeloma (MM) cell lines NCI-H929, ANBL-6, XG-1 and UM-3 used in this study were described earlier [41]. All cell lines were maintained in Iscove's Modified Dulbecco's Medium (IMDM) (Gibco Life Technologies, Bleiswijk, The Netherlands) supplemented with 2 mM L-glutamine, 100 U/ mL penicillin, 100 μg/mL streptomycin and 10% fetal calf serum (FCS).…”

Section: Cell Lines Primary Patient Samplesmentioning

confidence: 99%

The NEDD8-activating enzyme inhibitor MLN4924 induces DNA damage in Ph+ leukemia and sensitizes for ABL kinase inhibitors

et al. 2019

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The BCR-ABL1 fusion gene is the driver oncogene in chronic myeloid leukemia (CML) and Philadelphia-chromosome positive (Ph+) acute lymphoblastic leukemia (ALL). The introduction of tyrosine kinase inhibitors (TKIs) targeting the ABL kinase (such as imatinib) has dramatically improved survival of CML and Ph+ ALL patients. However, primary and acquired resistance to TKIs remains a clinical challenge. Ph+ leukemia patients who achieve a complete cytogenetic (CCR) or deep molecular response (MR) (≥4.5log reduction in BCR-ABL1 transcripts) represent long-term survivors. Thus, the fast and early eradication of leukemic cells predicts MR and is the prime clinical goal for these patients. We show here that the first-in-class inhibitor of the Nedd8-activating enzyme (NAE1) MLN4924 effectively induced caspase-dependent apoptosis in Ph+ leukemia cells, and sensitized leukemic cells for ABL tyrosine kinase inhibitors (TKI) and hydroxyurea (HU). We demonstrate that MLN4924 induced DNA damage in Ph+ leukemia cells by provoking the activation of an intra S-phase checkpoint, which was enhanced by imatinib co-treatment. The combination of MLN4924 and imatinib furthermore triggered a dramatic shift in the expression of MCL1 and NOXA. Our data offers a clear rationale to explore the clinical activity of MLN4924 (alone and in combination with ABL TKI) in Ph+ leukemia patients

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Aberrantly expressed LGR4 empowers Wnt signaling in multiple myeloma by hijacking osteoblast-derived R-spondins

Cited by 37 publications

References 63 publications

BMP9 Reduces Bone Loss in Ovariectomized Mice by Dual Regulation of Bone Remodeling

BMP9 Reduces Bone Loss in Ovariectomized Mice by Dual Regulation of Bone Remodeling

Syndecan-1 promotes Wnt/β-catenin signaling in multiple myeloma by presenting Wnts and R-spondins

The NEDD8-activating enzyme inhibitor MLN4924 induces DNA damage in Ph+ leukemia and sensitizes for ABL kinase inhibitors

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