MEIS1-mediated transactivation of synaptotagmin-like 1 promotes CXCL12/CXCR4 signaling and leukemogenesis

Yokoyama, Takashi; Nakatake, Mayuka; Kuwata, Takeshi; Couzinet, Arnaud; Goitsuka, Ryo; Tsutsumi, Sadami; Aburatani, Hiroyuki; Valk, Peter J.M.; Delwel, Ruud; Nakamura, Takuro

doi:10.1172/jci81516

Cited by 36 publications

(35 citation statements)

References 66 publications

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“…Consequently, as a response to increased cytokines in the MM BM microenvironment, signalling molecules involved in the JAK/STAT pathway and WNT signalling pathway may mediate M2 polarization by increasing TRIB1 and CXCL12 / CXCR4 expression in monocytes. Activation of the CXCL12/CXCR4 axis upregulates TRIB1 gene expression through HOXA9/MEIS1 expression (Jin et al , ) The CXCL12/CXCR4 axis, which we show is overactive in MM BM, has been shown to also upregulate MUC1 and CD44 gene expression (Yokoyama et al , ; Yin et al , ). M2 macrophages induced by MM in turn upregulate both MUC1 and CD44 on tumour cells (Fig A).…”

Section: Discussionmentioning

confidence: 58%

JAK1/2 pathway inhibition suppresses M2 polarization and overcomes resistance of myeloma to lenalidomide by reducing TRIB1, MUC1, CD44, CXCL12, and CXCR4 expression

Chen

Sanchez

et al. 2019

Br J Haematol

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Monocytes polarize into pro-inflammatory macrophage-1 (M1) or alternative macrophage-2 (M2) states with distinct phenotypes and physiological functions. M2 cells promote tumour growth and metastasis whereas M1 macrophages show anti-tumour effects. We found that M2 cells were increased whereas M1 cells were decreased in bone marrow (BM) from multiple myeloma (MM) patients with progressive disease (PD) compared to those in complete remission (CR). Gene expression of Tribbles homolog 1 (TRIB1) protein kinase, an inducer of M2 polarization, was increased in BM from MM patients with PD compared to those in CR. Ruxolitinib (RUX) is an inhibitor of the Janus kinase family of protein tyrosine kinases (JAKs) and is effective for treating patients with myeloproliferative disorders. RUX markedly reduces both M2 polarization and TRIB1 gene expression in MM both in vitro and in vivo in human MM xenografts in severe combined immunodeficient mice. RUX also downregulates the expression of CXCL12, CXCR4, MUC1, and CD44 in MM cells and monocytes co-cultured with MM tumour cells; overexpression of these genes is associated with resistance of MM cells to the immunomodulatory agent lenalidomide. These results provide the rationale for evaluation of JAK inhibitors, including MM BM in combination with lenalidomide, for the treatment of MM patients.

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Section: Discussionmentioning

confidence: 58%

JAK1/2 pathway inhibition suppresses M2 polarization and overcomes resistance of myeloma to lenalidomide by reducing TRIB1, MUC1, CD44, CXCL12, and CXCR4 expression

Chen

Sanchez

et al. 2019

Br J Haematol

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“…The murine HT MG-430 PM array (Affymetrix) was hybridized with aRNA probes generated from eMC 48 h after transduction with pMYs- CIC-DUX4 or empty vector, CDS and ES tumor tissues, or a mixture of mouse normal tissues according to methods described previously (11). The expression data were analyzed using GeneSpring ver 12.6 (Agilent Technologies) and gene set enrichment analysis (GSEA) was performed using GSEA-P 2.0 software (12).…”

Section: Methodsmentioning

confidence: 99%

CIC-DUX4 Induces Small Round Cell Sarcomas Distinct from Ewing Sarcoma

et al. 2017

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CIC-DUX4 sarcoma (CDS) or CIC-rearranged sarcoma is a subcategory of small round cell sarcoma resembling the morphological phenotypes of Ewing sarcoma (ES). Hoever, recent clinicopathologic and molecular genetic analyses indicate that CDS is an independent disease entity from ES. Few ancillary markers have been used in the differential diagnosis of CDS, and additional CDS-specific biomarkers are needed for more definitive classification. Here we report the generation of an ex vivo mouse model for CDS by transducing embryonic mesenchymal cells (eMC) with human CIC-DUX4 cDNA. Recipient mice transplanted with eMC expressing CIC-DUX4 rapidly developed an aggressive, undifferentiated sarcoma composed of small-round to short-spindle cells. Gene expression profiles of CDS and eMC revealed upregulation of CIC-DUX4 downstream genes such as PEA3 family genes, Ccnd2, Crh and Zic1. Immunohistochemical analyses for both mouse and human tumors showed that CCND2 and MUC5AC are reliable biomarkers to distinguish CDS from ES. Gene silencing of CIC-DUX4 as well as Ccnd2, Ret, and Bcl2 effectively inhibited CDS tumor growth in vitro. The CDK4/6 inhibitor palbociclib and the soft tissue sarcoma drug trabectedin also blocked the growth of mouse CDS. In summary, our mouse model provides important biological information about CDS and provides a useful platform to explore biomarkers and therapeutic agents for CDS.

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“…Chromatin immunoprecipitation and sequencing was carried out using the method previously described with modifications . A total of 5 × 10 7 cells per immunoprecipitation were fixed with 1% formaldehyde for 10 minutes at 37°C.…”

Section: Methodsmentioning

confidence: 99%

“…Chromatin immunoprecipitation and sequencing was carried out using the method previously described with modifications. 14 roadinstitute.org/software/igv). EWS-FLI1-binding motifs were searched using the AME (MEME-Suit Version 4.12.0) program (http://meme-suite.org/index.html).…”

Section: Chromatin Immunoprecipitation and Sequencingmentioning

confidence: 99%

EWS‐FLI1 regulates a transcriptional program in cooperation with Foxq1 in mouse Ewing sarcoma

et al. 2018

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EWS‐FLI1 constitutes an oncogenic transcription factor that plays key roles in Ewing sarcoma development and maintenance. We have recently succeeded in generating an ex vivo mouse model for Ewing sarcoma by introducing EWS‐FLI1 into embryonic osteochondrogenic progenitors. The model well recapitulates the biological characteristics, small round cell morphology, and gene expression profiles of human Ewing sarcoma. Here, we clarified the global DNA binding properties of EWS‐FLI1 in mouse Ewing sarcoma. GGAA microsatellites were found to serve as binding sites of EWS‐FLI1 albeit with less frequency than that in human Ewing sarcoma; moreover, genomic distribution was not conserved between human and mouse. Nevertheless, EWS‐FLI1 binding sites within GGAA microsatellites were frequently associated with the histone H3K27Ac enhancer mark, suggesting that EWS‐FLI1 could affect global gene expression by binding its target sites. In particular, the Fox transcription factor binding motif was frequently observed within EWS‐FLI1 peaks and Foxq1 was identified as the cooperative partner that interacts with the EWS portion of EWS‐FLI1. Trib1 and Nrg1 were demonstrated as target genes that are co‐regulated by EWS‐FLI1 and Foxq1, and are important for cell proliferation and survival of Ewing sarcoma. Collectively, our findings present novel aspects of EWS‐FLI1 function as well as the importance of GGAA microsatellites.

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MEIS1-mediated transactivation of synaptotagmin-like 1 promotes CXCL12/CXCR4 signaling and leukemogenesis

Cited by 36 publications

References 66 publications

JAK1/2 pathway inhibition suppresses M2 polarization and overcomes resistance of myeloma to lenalidomide by reducing TRIB1, MUC1, CD44, CXCL12, and CXCR4 expression

JAK1/2 pathway inhibition suppresses M2 polarization and overcomes resistance of myeloma to lenalidomide by reducing TRIB1, MUC1, CD44, CXCL12, and CXCR4 expression

CIC-DUX4 Induces Small Round Cell Sarcomas Distinct from Ewing Sarcoma

EWS‐FLI1 regulates a transcriptional program in cooperation with Foxq1 in mouse Ewing sarcoma

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