Research Papers:

Toll-like receptor genetic variations in bone marrow transplantation

Kaori Uchino, Shohei Mizuno, Aiko Sato-Otsubo, Yasuhito Nannya, Motonori Mizutani, Tomohiro Horio, Ichiro Hanamura, J. Luis Espinoza, Makoto Onizuka, Koichi Kashiwase, Yasuo Morishima, Takahiro Fukuda, Yoshihisa Kodera, Noriko Doki, Koichi Miyamura, Takehiko Mori, Seishi Ogawa and Akiyoshi Takami _

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Oncotarget. 2017; 8:45670-45686. https://doi.org/10.18632/oncotarget.17315

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Kaori Uchino1, Shohei Mizuno1, Aiko Sato-Otsubo2, Yasuhito Nannya2, Motonori Mizutani1, Tomohiro Horio1, Ichiro Hanamura1, J. Luis Espinoza3, Makoto Onizuka4, Koichi Kashiwase5, Yasuo Morishima6, Takahiro Fukuda7, Yoshihisa Kodera8, Noriko Doki9, Koichi Miyamura10, Takehiko Mori11, Seishi Ogawa2 and Akiyoshi Takami1

1Division of Hematology, Department of Internal Medicine, Aichi Medical University School of Medicine, Nagakute, Japan

2Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan

3Cellular Transplantation Biology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan

4Department of Hematology and Oncology, Tokai University School of Medicine, Isehara, Japan

5Japanese Red Cross Kanto-Koshinetsu Block Blood Center, Tokyo, Japan

6Division of Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya, Japan

7Hematopoietic Stem Cell Transplantation Unit, National Cancer Center Hospital, Tokyo, Japan

8Department of Promotion for Blood and Marrow Transplantation, Aichi Medical University, Nagakute, Japan

9Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo, Japan

10Department of Hematology, Japanese Red Cross Nagoya First Hospital, Nagoya, Japan

11Division of Hematology, Department of Medicine, Keio University School of Medicine, Tokyo, Japan

Correspondence to:

Akiyoshi Takami, email: [email protected]

Keywords: toll-like receptor, unrelated donor, bone marrow transplantation, single nucleotide variation

Received: March 15, 2017    Accepted: March 31, 2017    Published: April 21, 2017


The Toll-like receptor family mediates the innate immune system through recognizing the molecular patterns of microorganisms and self-components and leading the synthesis of the inflammatory mediators. We retrospectively examined whether or not genetic variations in toll-like receptor 1 (rs5743551, -7202GQ>A), toll-like receptor 2 (rs7656411, 22215G>T), and toll-like receptor 4 (rs11536889, +3725G>C) affected transplant outcomes in a cohort of 365 patients who underwent unrelated HLA-matched bone marrow transplantation (for hematologic malignancies through the Japan Marrow Donor Program. Only donor toll-like receptor 4 variation significantly improved the survival outcomes. A multivariate analysis showed that the donor toll-like receptor 4 +3725G/G genotype was significantly associated with a better 5-year progression-free survival and a lower 5-year transplant-related mortality than other variations. Furthermore, the donor toll-like receptor 4 +3725G/G genotype was associated with a significantly lower incidence of fatal infections than other variations. The validation study of 502 patients confirmed that the donor toll-like receptor 4 +3725G/G genotype was associated with better survival outcomes. Toll-like receptor4 genotyping in transplant donors may therefore be a useful tool for optimizing donor selection and evaluating pretransplantation risks.

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