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Elevated expression of HMGB1 is prognostic of poor survival in patients with relapsed/refractory T/NK-CL

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Abstract

Despite the clinical value of HMGB1 in non-Hodgkin lymphoma (NHL), the impact of HMGB1 protein expression on survival of patients with mature T-cell and NK-cell lymphoma (T/NK-CL) is unknown. Here, we evaluated correlations of HMGB1 expression in tumor tissues with pathophysiological characteristics of disease and determined the prognostic value of HMGB1 expression in relapsed/refractory T/NK-CL. HMGB1 expression was detected by immunohistochemistry (IHC) in 66 cases of relapsed/refractory T/NK-CL, and specimens were classified as high or low HMGB1 expression. Univariate and multivariate Cox regression analyses identified prognostic factors associated with progression-free survival (PFS) and overall survival (OS). High HMGB1 expression was significantly correlated with increased Ki67 levels and progressive lymphoma subtypes. Univariate Cox regression analysis showed that high HMGB1 expression was associated with unfavorable PFS (P = 0.006) and poorer OS (P < 0.001). Prognostic factors identified by univariate analysis were prognostic index for peripheral T-cell lymphoma non-specified (PIT) score ≥ 2, bone marrow involvement, Ki67 ≥ 70%, and high HMGB1 expression. Multivariate Cox regression analysis revealed that high HMGB1 expression was an independent prognostic factor for poorer PFS [hazard ratio (HR) 3.593; 95% confidence interval (CI) 1.171–11.027; P = 0.025] and OS [HR 7.663; 95% CI 2.367–24.803; P = 0.001]. A proposal prognostic model combining HMGB1 and Ki67 expression showed improved prognostic capacity and may help guide treatment planning. High HMGB1 expression may be a promising prognostic predictor and a potential therapeutic target for relapsed/refractory T/NK-CL. Furthermore, to apply HMGB1 as one of the best bio-maker, an external independent control cohort is needed.

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References

  1. Swerdlow SH, Campo E, Pileri SA, Harris NL, Stein H, Siebert R, Advani R, Ghielmini M, Salles GA, Zelenetz AD, Jaffe ES (2016) The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood 127(20):2375–2390

    Article  CAS  Google Scholar 

  2. Adams SV, Newcomb PA, Shustov AR (2016) Racial patterns of peripheral T-cell lymphoma incidence and survival in the United States. J Clin Oncol 34(9):963–971

    Article  CAS  Google Scholar 

  3. Vose J, Armitage J, Weisenburger D, International T-Cell Lymphoma Project (2008) International peripheral T-cell and natural killer/T-cell lymphoma study: pathology findings and clinical outcomes. J Clin Oncol 26(25):4124–4130

    Article  Google Scholar 

  4. Yang H, Antoine DJ, Andersson U, Tracey KJ (2013) The many faces of HMGB1: molecular structure-functional activity in inflammation, apoptosis, and chemotaxis. J Leukoc Biol 93(6):865–873

    Article  CAS  Google Scholar 

  5. Kang R, Chen R, Zhang Q, Hou W, Wu S, Cao L, Huang J, Yu Y, Fan XG, Yan Z, Sun X, Wang H, Wang Q, Tsung A, Billiar TR, Zeh HJ III, Lotze MT, Tang D (2014) HMGB1 in health and disease. Mol Asp Med 40:1–116

    Article  CAS  Google Scholar 

  6. Kang R, Z Q, Zeh HJ 3rd, Lotze MT, Tang D (2013c) HMGB1 in cancer: good, bad, or both? Clin Cancer Res 19(15):4046–4057

    Article  CAS  Google Scholar 

  7. Jiao Y, Wang H-c, Fan S-j (2007) Growth suppression and radiosensitivity increase by HMGB1 in breast cancer. Acta Pharmacol Sin 28(12):1957–1967

    Article  CAS  Google Scholar 

  8. Takahashi Y, Hori T, Cooper TK, Liao J, Desai N, Serfass JM, Young MM, Park S, Izu Y, Wang HG (2013) Bif-1 haploinsufficiency promotes chromosomal instability and accelerates Myc-driven lymphomagenesis via suppression of mitophagy. Blood 121(9):1622–1632

    Article  CAS  Google Scholar 

  9. Bao G, Qiao Q, Zhao H, He X (2010) Prognostic value of HMGB1 overexpression in resectable gastric adenocarcinomas. World J Surg Oncol 8:52–52

    Article  Google Scholar 

  10. Meyer A, Staratschek-Jox A, Springwald A, Wenk H, Wolf J, Wickenhauser C, Bullerdiek J (2008) Non-Hodgkin lymphoma expressing high levels of the danger-signalling protein HMGB1. Leuk Lymphoma 49(6):1184–1189

    Article  CAS  Google Scholar 

  11. Tian et al (2019) Blockade of HMGB1 signaling pathway by ethyl pyruvate inhibits tumor growth in diffuse large B-cell lymphoma. Cell Death Dis 10(5):330–330

    Article  Google Scholar 

  12. Nguyen AH, Bhavsar SB, Riley EM, Caponetti GC, Agrawal DK (2016) Association of high mobility group BOX-1 and receptor for advanced glycation endproducts with clinicopathological features of haematological malignancies: a systematic review. Contemp Oncol (Pozn) 20(6):425–429

    CAS  Google Scholar 

  13. Kimura R, M N (2014) Abundant expression of HMGB1 in human T-cell lymphotropic virus type I-infected T-cell lines and high plasma levels of HMGB1 in patients with adult T-cell leukemia. Oncol Lett 7:1239–1242

    Article  CAS  Google Scholar 

  14. Inoue Y, Saito T, Ogawa K, Nishio Y, Kosugi S, Suzuki Y, Sakai H, Kato M, Takahashi M, Miura I (2013) Role of serum high mobility group box 1 in hematological malignancies complicated with systemic inflammatory response syndrome and effect of recombinant thrombomodulin. Leuk Lymphoma 54(9):1953–1958

    Article  CAS  Google Scholar 

  15. Mendonca Gorgulho C et al (2019) Different measures of HMGB1 location in cancer immunology. Methods Enzymol 629:195–217

    Article  Google Scholar 

  16. Hongo K, Kazama S, Tsuno NH, Ishihara S, Sunami E, Kitayama J, Watanabe T (2015) Immunohistochemical detection of high-mobility group box 1 correlates with resistance of preoperative chemoradiotherapy for lower rectal cancer: a retrospective study. World J Surg Oncol 13:7–7

    Article  Google Scholar 

  17. Ellin F, Landström J, Jerkeman M, Relander T (2014) Real-world data on prognostic factors and treatment in peripheral T-cell lymphomas: a study from the Swedish Lymphoma Registry. Blood 124(10):1570–1577

    Article  CAS  Google Scholar 

  18. Li Z-M, Huang JJ, Xia Y, Zhu YJ, Zhao W, Wei WX, Jiang WQ, Lin TY, Huang HQ, Guan ZZ (2012) High Ki-67 expression in diffuse large B-cell lymphoma patients with non-germinal center subtype indicates limited survival benefit from R-CHOP therapy. Eur J Haematol 88(6):510–517

    Article  Google Scholar 

  19. Song M-K, Chung JS, Joo YD, Lee SM, Oh SY, Shin DH, Yun EY, Kim SG, Seol YM, Shin HJ, Choi YJ, Cho GJ (2011) Clinical importance of Bcl-6-positive non-deep-site involvement in non-HIV-related primary central nervous system diffuse large B-cell lymphoma. J Neuro-Oncol 104(3):825–831

    Article  CAS  Google Scholar 

  20. Senda N, M T, Kamijo H, Nakajima R, Oka T, Takahashi N, Suga H, Yoshizaki A, Asano Y, Sugaya M, Sato S (2018) Increased HMGB1 levels in lesional skin and sera in patients with cutaneous T-cell lymphoma. Eur J Dermatol 28(5):621–627

    CAS  PubMed  Google Scholar 

  21. Mao XJ, Wang GF, Chen ZJ, Wang LN, Zhang JB, Wang HL (2012) Expression of HMGB1 and its clinical significance in T-cell lymphoma. Asian Pac J Cancer Prev 13(11):5569–5571

    Article  Google Scholar 

  22. Sitthinamsuwan P, Pattanaprichakul P, Treetipsatit J, Pongpruttipan T, Sukpanichnant S, Pincus LB, McCalmont TH (2018) Subcutaneous Panniculitis-Like T-Cell Lymphoma Versus Lupus Erythematosus Panniculitis: Distinction by Means of the Periadipocytic Cell Proliferation Index. Am J Dermatopathol 40(8):567–574

    Article  Google Scholar 

  23. Harris HE, Andersson U, Pisetsky DS (2012) HMGB1: a multifunctional alarmin driving autoimmune and inflammatory disease. Nature reviews. Rheumatology 8(4):195–202

    CAS  PubMed  Google Scholar 

  24. Jiang W, Wang Z, Li X, Fan X, Duan Y (2012) High-mobility group box 1 is associated with clinicopathologic features in patients with hepatocellular carcinoma. Pathol Oncol Res 18(2):293–298

    Article  CAS  Google Scholar 

  25. Fucikova J, Moserova I, Truxova I, Hermanova I, Vancurova I, Partlova S, Fialova A, Sojka L, Cartron PF, Houska M, Rob L, Bartunkova J, Spisek R (2014) High hydrostatic pressure induces immunogenic cell death in human tumor cells. Int J Cancer 135(5):1165–1177

    Article  CAS  Google Scholar 

  26. Gutierrez-Garcia G et al (2011) Comparison of four prognostic scores in peripheral T-cell lymphoma. Ann Oncol 22(2):397–404

    Article  CAS  Google Scholar 

  27. Lee J, Suh C, Park YH, Ko YH, Bang SM, Lee JH, Lee DH, Huh J, Oh SY, Kwon HC, Kim HJ, Lee SI, Kim JH, Park J, Oh SJ, Kim K, Jung C, Park K, Kim WS (2006) Extranodal natural killer T-cell lymphoma, nasal-type: a prognostic model from a retrospective multicenter study. J Clin Oncol 24(4):612–618

    Article  Google Scholar 

  28. Szczuraszek K, Mazur G, Jeleń M, Dziegiel P, Surowiak P, Zabel M (2008) Prognostic significance of Ki-67 antigen expression in non-Hodgkin's lymphomas. Anticancer Res 28(2A):1113–1118

    PubMed  Google Scholar 

  29. Zeng L, Huang W, Cao Z, Zheng B, Liu X, Guo L, Feng X (2019) The correlation of clinicopathological features and prognosis in extranodal natural killer/T cell lymphoma: a report of 42 cases in the early stage. Ann Hematol 98(6):1467–1476

    Article  CAS  Google Scholar 

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Funding

This study was funded by the National Natural Science Foundation of China (project number: 81872902, 81611130, and 81472759), the Guangdong Natural Science Foundation (project number: S2013010016331), and the Medical Research Foundation of Guangdong Province (nos. A2020145).

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Author notes

  1. Caiqin Wang, Yu Wang, Jianghua Cao, Jiajia Huang and Zhiming Li contributed equally to this work.

Authors and Affiliations

  1. Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510060, People’s Republic of China

    Caiqin Wang, Yu Wang, Jianghua Cao, Xiaoqing Sun, Xiaohua He, Peng Sun, Tianxiao Gao, Jiajia Huang & Zhiming Li

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  1. Caiqin Wang
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  2. Yu Wang
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Correspondence to Jiajia Huang or Zhiming Li.

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Wang, C., Wang, Y., Cao, J. et al. Elevated expression of HMGB1 is prognostic of poor survival in patients with relapsed/refractory T/NK-CL. Ann Hematol 100, 2293–2302 (2021). https://doi.org/10.1007/s00277-021-04473-4

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