Midostaurin reduces Regulatory T cells markers in Acute Myeloid Leukemia

作者: Lucas Gutierrez , Miran Jang , Tian Zhang , Mojtaba Akhtari , Houda Alachkar

DOI: 10.1038/S41598-018-35978-0

关键词: MyeloidLeukemiaMidostaurinT cellCancer researchStem cellMyeloid leukemiaMedicinePopulationFOXP3

摘要: Acute myeloid leukemia (AML) is a heterogeneous hematological malignancy in which the only curative approach allogeneic stem cell transplant (Allo-HSCT). The recognition and elimination of leukemic clones by donor T-cells contribute significantly to Allo-HSCT success. FLT3-ITD, common mutation AML, associated with poor prognosis. Recently, midostaurin became first FDA approved FLT3-inhibitor for pre-transplant patients FLT3-ITD combination standard therapy. In addition their multikinase activity may affect T-cell signaling, FLT3-inhibitors induce apoptosis malignant cells also enhance antigen presentation activate T-cells. Considering increased clinical use these inhibitors limited benefit derived from as single agents, understanding how T population function needed improve benefit. We examined effect four different FLT3 (midostaurin, sorafenib, tandutinib, quizartenib) on populations peripheral blood mononuclear (PBMC) obtained healthy donors AML. Midostaurin exhibited significant decrease CD4 + CD25 + FOXP3+ FOXP3 mRNA expression AML PBMCs. Similarly, samples collected treated showed reduction Tregs markers. Interferon-γ(IFN-γ), tumor necrosis factor-α(TNF-α), IL-10 levels were reduced following treatment. approval setting, our finding will have important implication it provides rationale functional investigation post-transplant patients.

参考文章(28)
Afonso R. M. Almeida, Nicolas Legrand, Martine Papiernik, António A. Freitas, Homeostasis of peripheral CD4+ T cells: IL-2R alpha and IL-2 shape a population of regulatory cells that controls CD4+ T cell numbers. Journal of Immunology. ,vol. 169, pp. 4850- 4860 ,(2002) , 10.4049/JIMMUNOL.169.9.4850
V. Di Caro, A. D'Anneo, B. Phillips, C. Engman, J. Harnaha, R. Lakomy, A. Styche, M. Trucco, N. Giannoukakis, Interleukin-7 matures suppressive CD127(+) forkhead box P3 (FoxP3)(+) T cells into CD127(-) CD25(high) FoxP3(+) regulatory T cells. Clinical and Experimental Immunology. ,vol. 165, pp. 60- 76 ,(2011) , 10.1111/J.1365-2249.2011.04334.X
Matthew A. Burchill, Jianying Yang, Christine Vogtenhuber, Bruce R. Blazar, Michael A. Farrar, IL-2 Receptor β-Dependent STAT5 Activation Is Required for the Development of Foxp3+ Regulatory T Cells Journal of Immunology. ,vol. 178, pp. 280- 290 ,(2007) , 10.4049/JIMMUNOL.178.1.280
Andrey Antov, Lili Yang, Monika Vig, David Baltimore, Luk Van Parijs, Essential role for STAT5 signaling in CD25+CD4+ regulatory T cell homeostasis and the maintenance of self-tolerance. Journal of Immunology. ,vol. 171, pp. 3435- 3441 ,(2003) , 10.4049/JIMMUNOL.171.7.3435
Mojgan Ahmadzadeh, Steven A. Rosenberg, IL-2 administration increases CD4+CD25hi Foxp3+ regulatory T cells in cancer patients Blood. ,vol. 107, pp. 2409- 2414 ,(2006) , 10.1182/BLOOD-2005-06-2399
Federico Simonetta, Nicolas Gestermann, Kim Zita Martinet, Michele Boniotto, Pierre Tissières, Benedict Seddon, Christine Bourgeois, Interleukin-7 Influences FOXP3+CD4+ Regulatory T Cells Peripheral Homeostasis PLoS ONE. ,vol. 7, pp. e36596- ,(2012) , 10.1371/JOURNAL.PONE.0036596
Yuichi Okutani, Akira Kitanaka, Terukazu Tanaka, Hiroshi Kamano, Hiroaki Ohnishi, Yoshitsugu Kubota, Toshihiko Ishida, Jiro Takahara, Src directly tyrosine-phosphorylates STAT5 on its activation site and is involved in erythropoietin-induced signaling pathway. Oncogene. ,vol. 20, pp. 6643- 6650 ,(2001) , 10.1038/SJ.ONC.1204807
Yan Jin, Hae Joo Wi, Min-Ho Choi, Sung-Tae Hong, Young Mee Bae, Regulation of anti-inflammatory cytokines IL-10 and TGF-β in mouse dendritic cells through treatment with Clonorchis sinensis crude antigen Experimental and Molecular Medicine. ,vol. 46, ,(2014) , 10.1038/EMM.2013.144
Joerg Ermann, Kathryn Drago, C Garrison Fathman, Samuel Strober, Robert S Negrin, Matthias Edinger, Petra Hoffmann, CD4+CD25+ regulatory T cells preserve graft-versus-tumor activity while inhibiting graft-versus-host disease after bone marrow transplantation. Nature Medicine. ,vol. 9, pp. 1144- 1150 ,(2003) , 10.1038/NM915