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Open Access 01-12-2016 | Research

CD274 promotes cell cycle entry of leukemia-initiating cells through JNK/Cyclin D2 signaling

Authors: Xia Fang, Chiqi Chen, Fangzhen Xia, Zhuo Yu, Yaping Zhang, Feifei Zhang, Hao Gu, Jiangbo Wan, Xiaocui Zhang, Wei Weng, Cheng Cheng Zhang, Guo-Qiang Chen, Aibing Liang, Li Xie, Junke Zheng

Published in: Journal of Hematology & Oncology | Issue 1/2016

Abstract

Background

CD274 (programmed death ligand 1, also known as B7H1) is expressed in both solid tumors and hematologic malignancies and is of critical importance for the escape of tumor cells from immune surveillance by inhibiting T cell function via its receptor, programmed death 1 (PD-1). Increasing evidence indicates that functional monoclonal antibodies of CD274 may potently enhance the antitumor effect in many cancers. However, the role of CD274 in leukemia-initiating cells (LICs) remains largely unknown.

Methods

We established an MLL-AF9-induced acute myeloid leukemia (AML) model with wild-type (WT) and CD274-null mice to elucidate the role of CD274 in the cell fates of LICs, including self-renewal, differentiation, cell cycle, and apoptosis. RNA sequencing was performed to reveal the potential downstream targets, the results of which were further validated both in vitro and in vivo.

Results

In silico analysis indicated that CD274 level was inversely correlated with the overall survival of AML patients. In Mac-1⁺/c-Kit⁺ mouse LICs, CD274 was expressed at a much higher level than in the normal hematopoietic stem cells (HSCs). The survival of the mice with CD274-null leukemia cells was dramatically extended during the serial transplantation compared with that of their WT counterparts. CD274 deletion led to a significant decrease in LIC frequency and arrest in the G1 phase of the cell cycle. Interestingly, CD274 is not required for the maintenance of HSC pool as shown in our previous study. Mechanistically, we demonstrated that the levels of both phospho-JNK and Cyclin D2 were strikingly downregulated in CD274-null LICs. The overexpression of Cyclin D2 fully rescued the loss of function of CD274. Moreover, CD274 was directly associated with JNK and enhanced the downstream signaling to increase the Cyclin D2 level, promoting leukemia development.

Conclusions

The surface immune molecule CD274 plays a critical role in the proliferation of LICs. The CD274/JNK/Cyclin D2 pathway promotes the cell cycle entry of LICs, which may serve as a novel therapeutic target for the treatment of leukemia.

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Estey E, Dohner H. Acute myeloid leukaemia. Lancet. 2006;368:1894–907.CrossRefPubMed

Pulte D, Gondos A, Brenner H. Improvements in survival of adults diagnosed with acute myeloblastic leukemia in the early 21st century. Haematologica. 2008;93:594–600.CrossRefPubMed

Middeke JM, Beelen D, Stadler M, Gohring G, Schlegelberger B, Baurmann H, Bug G, Bellos F, Mohr B, Buchholz S, Schwerdtfeger R, Martin H, Hegenbart U, Ehninger G, Bornhäuser M, Schetelig J, Cooperative German Transplant Study Group. Outcome of high-risk acute myeloid leukemia after allogeneic hematopoietic cell transplantation: negative impact of abnl(17p) and -5/5q. Blood. 2012;120:2521–8.CrossRefPubMed

Paietta E. Minimal residual disease in acute myeloid leukemia: coming of age. Hematology Am Soc Hematol Educ Program. 2012;2012:35–42.PubMed

Kantarjian H, Ravandi F, O'Brien S, Cortes J, Faderl S, Garcia-Manero G, Jabbour E, Wierda W, Kadia T, Pierce S, Shan J, Keating M, Freireich EJ. Intensive chemotherapy does not benefit most older patients (age 70 years or older) with acute myeloid leukemia. Blood. 2010;116:4422–9.CrossRefPubMedPubMedCentral

Zheng J, Umikawa M, Cui C, Li J, Chen X, Zhang C, Huynh H, Kang X, Silvany R, Wan X, Ye J, Cantó AP, Chen SH, Wang HY, Ward ES, Zhang CC. Inhibitory receptors bind ANGPTLs and support blood stem cells and leukaemia development. Nature. 2012;485:656–60.CrossRefPubMedPubMedCentral

Zhang F, Zheng J, Kang X, Deng M, Lu Z, Kim J, Zhang C. Inhibitory leukocyte immunoglobulin-like receptors in cancer development. Sci China Life Sci. 2015;58:1216–25.CrossRefPubMed

Jaiswal S, Jamieson CH, Pang WW, Park CY, Chao MP, Majeti R, Traver D, van Rooijen N, Weissman IL. CD47 is upregulated on circulating hematopoietic stem cells and leukemia cells to avoid phagocytosis. Cell. 2009;138:271–85.CrossRefPubMedPubMedCentral

Frolova O, Benito J, Brooks C, Wang RY, Korchin B, Rowinsky EK, Cortes J, Kantarjian H, Andreeff M, Frankel AE, Konopleva M. SL-401 and SL-501, targeted therapeutics directed at the interleukin-3 receptor, inhibit the growth of leukaemic cells and stem cells in advanced phase chronic myeloid leukaemia. Br J Haematol. 2014;166:862–74.CrossRefPubMedPubMedCentral

10.

Safaee M, Fakurnejad S, Bloch O, Clark AJ, Ivan ME, Sun MZ, Oh T, Phillips JJ, Parsa AT. Proportional upregulation of CD97 isoforms in glioblastoma and glioblastoma-derived brain tumor initiating cells. PLoS One. 2015;10, e0111532.CrossRefPubMedPubMedCentral

11.

van Pel M, Hagoort H, Hamann J, Fibbe WE. CD97 is differentially expressed on murine hematopoietic stem-and progenitor-cells. Haematologica. 2008;93:1137–44.CrossRefPubMed

12.

Majeti R, Chao MP, Alizadeh AA, Pang WW, Jaiswal S, Gibbs Jr KD, van Rooijen N, Weissman IL. CD47 is an adverse prognostic factor and therapeutic antibody target on human acute myeloid leukemia stem cells. Cell. 2009;138:286–99.CrossRefPubMedPubMedCentral

13.

Chao MP, Alizadeh AA, Tang C, Jan M, Weissman-Tsukamoto R, Zhao F, Park CY, Weissman IL, Majeti R. Therapeutic antibody targeting of CD47 eliminates human acute lymphoblastic leukemia. Cancer Res. 2011;71:1374–84.CrossRefPubMed

14.

Mardiros A, Forman SJ, Budde LE. T cells expressing CD123 chimeric antigen receptors for treatment of acute myeloid leukemia. Curr Opin Hematol. 2015;22:484–8.CrossRefPubMedPubMedCentral

15.

Agata Y, Kawasaki A, Nishimura H, Ishida Y, Tsubata T, Yagita H, Honjo T. Expression of the PD-1 antigen on the surface of stimulated mouse T and B lymphocytes. Int Immunol. 1996;8:765–72.CrossRefPubMed

16.

Chang WS, Kim JY, Kim YJ, Kim YS, Lee JM, Azuma M, Yagita H, Kang CY. Cutting edge. Programmed death-1/programmed death ligand 1 interaction regulates the induction and maintenance of invariant NKT cell anergy. J Immunol. 2008;181:6707–10.CrossRefPubMed

17.

Crane CA, Panner A, Murray JC, Wilson SP, Xu H, Chen L, Simko JP, Waldman FM, Pieper RO, Parsa AT. PI(3) kinase is associated with a mechanism of immunoresistance in breast and prostate cancer. Oncogene. 2009;28:306–12.CrossRefPubMed

18.

Crane C, Panner A, Pieper RO, Arbiser J, Parsa AT. Honokiol-mediated inhibition of PI3K/mTOR pathway: a potential strategy to overcome immunoresistance in glioma, breast, and prostate carcinoma without impacting T cell function. J Immunother. 2009;32:585–92.CrossRefPubMedPubMedCentral

19.

Concha-Benavente F, Srivastava RM, Trivedi S, Lei Y, Chandran U, Seethala RR, Freeman GJ, Ferris RL. Identification of the cell-intrinsic and -extrinsic pathways downstream of EGFR and IFNgamma that induce PD-L1 expression in head and neck cancer. Cancer Res. 2016;76:1031–43.CrossRefPubMed

20.

Fujita Y, Yagishita S, Hagiwara K, Yoshioka Y, Kosaka N, Takeshita F, Fujiwara T, Tsuta K, Nokihara H, Tamura T, Asamura H, Kawaishi M, Kuwano K, Ochiya T. The clinical relevance of the miR-197/CKS1B/STAT3-mediated PD-L1 network in chemoresistant non-small-cell lung cancer. Mol Ther. 2015;23:717–27.CrossRefPubMedPubMedCentral

21.

Dong L, Lv H, Li W, Song Z, Li L, Zhou S, Qiu L, Qian Z, Liu X, Feng L, Meng B, Fu K, Wang X, Pan-Hammarström Q, Wang P, Wang X, Zhang H. Co-expression of PD-L1 and p-AKT is associated with poor prognosis in diffuse large B-cell lymphoma via PD-1/PD-L1 axis activating intracellular AKT/mTOR pathway in tumor cells. Oncotarget. 2016;7:33350–62.PubMedPubMedCentral

22.

Schreiner B, Mitsdoerffer M, Kieseier BC, Chen L, Hartung HP, Weller M, Wiendl H. Interferon-beta enhances monocyte and dendritic cell expression of B7-H1 (PD-L1), a strong inhibitor of autologous T-cell activation: relevance for the immune modulatory effect in multiple sclerosis. J Neuroimmunol. 2004;155:172–82.CrossRefPubMed

23.

Ghebeh H, Lehe C, Barhoush E, Al-Romaih K, Tulbah A, Al-Alwan M, Hendrayani SF, Manogaran P, Alaiya A, Al-Tweigeri T, Aboussekhra A, Dermime S. Doxorubicin downregulates cell surface B7-H1 expression and upregulates its nuclear expression in breast cancer cells: role of B7-H1 as an anti-apoptotic molecule. Breast Cancer Res. 2010;12:R48.CrossRefPubMedPubMedCentral

24.

Krivtsov AV, Twomey D, Feng Z, Stubbs MC, Wang Y, Faber J, Levine JE, Wang J, Hahn WC, Gilliland DG, Golub TR, Armstrong SA. Transformation from committed progenitor to leukaemia stem cell initiated by MLL-AF9. Nature. 2006;442:818–22.CrossRefPubMed

25.

Zheng J, Huynh H, Umikawa M, Silvany R, Zhang CC. Angiopoietin-like protein 3 supports the activity of hematopoietic stem cells in the bone marrow niche. Blood. 2011;117:470–9.CrossRefPubMedPubMedCentral

26.

Zheng J, Umikawa M, Zhang S, Huynh H, Silvany R, Chen BP, Chen L, Zhang CC. Ex vivo expanded hematopoietic stem cells overcome the MHC barrier in allogeneic transplantation. Cell Stem Cell. 2011;9:119–30.CrossRefPubMedPubMedCentral

27.

Metzeler KH, Hummel M, Bloomfield CD, Spiekermann K, Braess J, Sauerland MC, Heinecke A, Radmacher M, Marcucci G, Whitman SP, Maharry K, Paschka P, Larson RA, Berdel WE, Büchner T, Wörmann B, Mansmann U, Hiddemann W, Bohlander SK, Buske C, Cancer and Leukemia Group B, German AML Cooperative Group. An 86-probe-set gene-expression signature predicts survival in cytogenetically normal acute myeloid leukemia. Blood. 2008;112:4193–201.CrossRefPubMedPubMedCentral

28.

Russo LC, Araujo CB, Iwai LK, Ferro ES, Forti FL. A Cyclin D2-derived peptide acts on specific cell cycle phases by activating ERK1/2 to cause the death of breast cancer cells. J Proteomics. 2016;doi:10.1016/j.jprot.2016.06.028.

29.

Turchi L, Loubat A, Rochet N, Rossi B, Ponzio G. Evidence for a direct correlation between c-Jun NH2 terminal kinase 1 activation, cyclin D2 expression, and G(1)/S phase transition in the murine hybridoma 7TD1 cells. Exp Cell Res. 2000;261:220–8.CrossRefPubMed

30.

McClanahan F, Hanna B, Miller S, Clear AJ, Lichter P, Gribben JG, Seiffert M. PD-L1 checkpoint blockade prevents immune dysfunction and leukemia development in a mouse model of chronic lymphocytic leukemia. Blood. 2015;126:203–11.CrossRefPubMedPubMedCentral

31.

Zhou Q, Munger ME, Highfill SL, Tolar J, Weigel BJ, Riddle M, Sharpe AH, Vallera DA, Azuma M, Levine BL, June CH, Murphy WJ, Munn DH, Blazar BR. Program death-1 signaling and regulatory T cells collaborate to resist the function of adoptively transferred cytotoxic T lymphocytes in advanced acute myeloid leukemia. Blood. 2010;116:2484–93.CrossRefPubMedPubMedCentral

32.

Zhang L, Gajewski TF, Kline J. PD-1/PD-L1 interactions inhibit antitumor immune responses in a murine acute myeloid leukemia model. Blood. 2009;114:1545–52.CrossRefPubMedPubMedCentral

33.

Daar IO. Non-SH2/PDZ reverse signaling by ephrins. Semin Cell Dev Biol. 2012;23:65–74.CrossRefPubMed

34.

Ishibashi M, Tamura H, Sunakawa M, Kondo-Onodera A, Okuyama N, Hamada Y, Moriya K, Choi I, Tamada K, Inokuchi K. Myeloma drug resistance induced by binding of myeloma B7-H1 (PD-L1) to PD-1. Cancer Immunol Res. 2016;4:779–88.CrossRefPubMed

35.

Song X, Liu J, Lu Y, Jin H, Huang D. Overexpression of B7-H1 correlates with malignant cell proliferation in pancreatic cancer. Oncol Rep. 2014;31:1191–8.PubMed

36.

Hsiao PC, Hsieh YH, Chow JM, Yang SF, Hsiao M, Hua KT, Lin CH, Chen HY, Chien MH. Hispolon induces apoptosis through JNK1/2-mediated activation of a caspase-8, -9, and -3-dependent pathway in acute myeloid leukemia (AML) cells and inhibits AML xenograft tumor growth in vivo. J Agric Food Chem. 2013;61:10063–73.CrossRefPubMed

37.

Zhao Q, Assimopoulou AN, Klauck SM, Damianakos H, Chinou I, Kretschmer N, Rios JL, Papageorgiou VP, Bauer R, Efferth T. Inhibition of c-MYC with involvement of ERK/JNK/MAPK and AKT pathways as a novel mechanism for shikonin and its derivatives in killing leukemia cells. Oncotarget. 2015;6:38934–51.PubMedPubMedCentral

38.

Calvino E, Tejedor MC, Sancho P, Herraez A, Diez JC. JNK and NFkappaB dependence of apoptosis induced by vinblastine in human acute promyelocytic leukaemia cells. Cell Biochem Funct. 2015;33:211–9.CrossRefPubMed

Title: CD274 promotes cell cycle entry of leukemia-initiating cells through JNK/Cyclin D2 signaling
Authors: Xia Fang
Chiqi Chen
Fangzhen Xia
Zhuo Yu
Yaping Zhang
Feifei Zhang
Hao Gu
Jiangbo Wan
Xiaocui Zhang
Wei Weng
Cheng Cheng Zhang
Guo-Qiang Chen
Aibing Liang
Li Xie
Junke Zheng
Publication date: 01-12-2016
Publisher: BioMed Central
Published in: Journal of Hematology & Oncology / Issue 1/2016
Electronic ISSN: 1756-8722
DOI: https://doi.org/10.1186/s13045-016-0350-6

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