MIF-Induced Stromal PKCβ/IL8 Is Essential in Human Acute Myeloid Leukemia

Abdul‐Aziz, Amina; Shafat, Manar S.; Mehta, Tarang K.; Palma, Federica Di; Lawes, Matthew; Rushworth, Stuart A.; Bowles, Kristian M.

doi:10.1158/0008-5472.can-16-1095

Cited by 76 publications

(50 citation statements)

References 43 publications

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“…Preclinical studies of milatuzumab have shown potent efficacy in hematopoietic neoplasms primarily occupying the BM niche, such as CLL/SLL, PCM, and AML . All CLL/SLL in the current study expressed CD74.…”

Section: Discussionmentioning

confidence: 64%

High frequency of CD74 expression in lymphomas: implications for targeted therapy using a novel anti‐CD74‐drug conjugate

Song

Molina

et al. 2018

The Journal of Pathology CR

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CD74 is a type II transmembrane glycoprotein that functions as an MHC class II chaperone and displays diverse roles in immune responses. Recently, anti-CD74 immunotherapy has shown promise as an effective treatment strategy for lymphoid neoplasms in preclinical models. Using a human anti-CD74 antibody (SP7219), we defined the expression of CD74 protein in both normal and over 790 neoplastic hematolymphoid tissue samples. We found that CD74 is expressed broadly in normal B-cell compartments including primary and secondary lymphoid follicles and in the thymic medulla. The vast majority of lymphomas expressed CD74, including Hodgkin lymphomas (98%), B-cell lymphomas (96%), extranodal NK/T-cell lymphomas (88%), mature T-cell lymphomas (80%), and plasma cell myeloma (75%). Our findings confirm and expand previous observations regarding the expression of CD74 and suggest that CD74 expression on tumor cells may be directly targeted for immunomodulatory therapy for lymphoid and plasma cell malignancies.

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Section: Discussionmentioning

confidence: 64%

High frequency of CD74 expression in lymphomas: implications for targeted therapy using a novel anti‐CD74‐drug conjugate

Song

Molina

et al. 2018

The Journal of Pathology CR

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“…1). In recent years, several studies have shown a paracrine effect of MSC‐secreted CXCL8 on tumors (30–32). Therefore, we also analyzed the CXCL8 expression levels in the MSCs obtained from the ex vivo expansion of BM cells from the patients and control subjects.…”

Section: Resultsmentioning

confidence: 99%

“…Several studies have shown increased synthesis of proinflammatory cytokines and chemokines, including that of CXCL8, in BM‐MSCs stimulated with cancer cells in vitro (32, 41, 42). Consistent with this, we found increased mRNA levels of CXCL8 in MSCs and AML cell cocultures compared with that of either monoculture.…”

Section: Discussionmentioning

confidence: 99%

CXCL8 derived from mesenchymal stromal cells supports survival and proliferation of acute myeloid leukemia cells through the PI3K/AKT pathway

Cheng

Liu

et al. 2018

FASEB j.

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The role of proinflammatory cytokines secreted by the bone marrow mesenchymal stromal cells (BM‐MSCs) in the progression of acute myeloid leukemia (AML) is poorly understood. We compared C‐X‐C motif chemokine ligand (CXCL)8 expression levels in the BM‐MSCs of patients with AML and normal control subjects and detected significantly higher levels in the former. Furthermore, CXCL8 was up‐regulated in cocultures of BM‐MSCs and leukemic cell lines compared with either monoculture. CXCL8 expression was significantly higher in MSCs compared with mononuclear cells in patients with de novo AML. To elucidate the function of paracrine CXCL8 in AML, we blocked CXCL8 binding to the C‐X‐C motif chemokine receptor (CXCR)2 in the AML cells using SB225002. Inhibition of CXCL8/CXCR2 binding decreased proliferation in the AML cells by inducing cell cycle arrest at the G0/G1 phase and apoptosis via decreased AKT phosphorylation. Blocking the PI3K/AKT signaling pathway by a specific inhibitor induced similar apoptosis induction and lower proliferation, suggesting that the PI3K/AKT signaling pathway was also involved in CXCL8 action. Taken together, our findings demonstrate that BM‐MSCs are the main source of CXCL8 in the AML bone marrow microenvironment and promote leukemogenesis via the PI3K/AKT signaling pathway, indicating a novel therapeutic target.—Cheng, J., Li, Y., Liu, S., Jiang, Y., Ma, J., Wan, L., Li, Q., Pang, T. CXCL8 derived from mesenchymal stromal cells supports survival and proliferation of acute myeloid leukemia cells through the PI3K/AKT pathway. FASEB J. 33,4755–4764 (2019). http://www.fasebj.org

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“…Given the high invasive potency of synovial sarcoma cells towards the surrounding tissue, it is possible that IL-8 contributes to the invasive activity of the tumor cells by interacting with the tumor microenvironment. Indeed, increased secretion of IL-8 secretions has been reported in various human malignancies, and IL-8 is involved in more aggressive phenotypes [38][39][40][41]. Functional modulation of tumor-associated neutrophils by IL-8 has also been described as a poor prognostic factor for malignancies [39,42].…”

Section: Discussionmentioning

confidence: 99%

Cooperation between SS18-SSX1 and miR-214 in Synovial Sarcoma Development and Progression

Tanaka

Homme

Yamazaki

et al. 2020

Cancers

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SS18-SSX fusion proteins play a central role in synovial sarcoma development, although, the genetic network and mechanisms of synovial sarcomagenesis remain unknown. We established a new ex vivo synovial sarcoma mouse model through retroviral-mediated gene transfer of SS18-SSX1 into mouse embryonic mesenchymal cells followed by subcutaneous transplantation into nude mice. This approach successfully induced subcutaneous tumors in 100% recipients, showing invasive proliferation of short spindle tumor cells with occasional biphasic appearance. Cytokeratin expression was observed in epithelial components in tumors and expression of TLE1 and BCL2 was also shown. Gene expression profiling indicated SWI/SNF pathway modulation by SS18-SSX1 introduction into mesenchymal cells and Tle1 and Atf2 upregulation in tumors. These findings indicate that the model exhibits phenotypes typical of human synovial sarcoma. Retroviral tagging of the tumor identified 15 common retroviral integration sites within the Dnm3 locus as the most frequent in 30 mouse synovial sarcomas. miR-199a2 and miR-214 upregulation within the Dnm3 locus was observed. SS18-SSX1 and miR-214 cointroduction accelerated sarcoma onset, indicating that miR-214 is a cooperative oncomiR in synovial sarcomagenesis. miR-214 functions in a cell non-autonomous manner, promoting cytokine gene expression (e.g., Cxcl15/IL8). Our results emphasize the role of miR-214 in tumor development and disease progression.

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MIF-Induced Stromal PKCβ/IL8 Is Essential in Human Acute Myeloid Leukemia

Cited by 76 publications

References 43 publications

High frequency of CD74 expression in lymphomas: implications for targeted therapy using a novel anti‐CD74‐drug conjugate

High frequency of CD74 expression in lymphomas: implications for targeted therapy using a novel anti‐CD74‐drug conjugate

CXCL8 derived from mesenchymal stromal cells supports survival and proliferation of acute myeloid leukemia cells through the PI3K/AKT pathway

Cooperation between SS18-SSX1 and miR-214 in Synovial Sarcoma Development and Progression

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