| 1. |
Mori Y, Takizawa J, Katsuoka Y, Takezako N, Nagafuji K, Handa H, Kuroda J, Sunami K, Kamimura T, Ogawa R, Kikushige Y, Harada M, Akashi K, Miyamoto T,, Autologous HSCT with novel agent-based induction and consolidation followed by lenalidomide maintenance for untreated multiple myeloma., Cancer Science, 2024.03. |
| 2. |
Hatakeyama, K., Kikushige, Y.*, Ishihara, D., Yamamoto, S., Kawano, G., Tochigi, T., Miyamoto, T., Sakoda, T., Christoforou, A., Kunisaki, Y., Fukata, M., Kato, K., Ito, T., Handa, H. & Akashi, K. , Thrombospondin-1 is an endogenous substrate of cereblon responsible for immunomodulatory drugs-induced thromboembolism. Blood Adv., Blood Advances, 2024.01. |
| 3. |
Sugio, T., Uchida, N., Miyawaki, K., Ohno, Y., Eto, T., Mori, Y., Yoshimoto, G., Kikushige, Y., Kunisaki, Y., Mizuno, S., Nagafuji, K., Iwasaki, H., Kamimura, T., Ogawa, R., Miyamoto, T., Taniguchi, S., Akashi, K. & Kato, K., Prognostic impact of HLA supertype mismatch in single-unit cord blood transplantation, Bone Marrow Transplant, 2024.03. |
| 4. |
Harada, T.*, Kikushige, Y.*, Miyamoto, T., Uno, K., Niiro, H., Kawakami, A., Koga, T., Akashi, K. & Yoshizaki, K. , Peripheral helper-T-cell-derived CXCL13 is a crucial pathogenic factor in idiopathic multicentric Castleman disease, Nature Communications, 2023.12. |
| 5. |
RHAMM marks proliferative subpopulation of human colorectal cancer stem cells, Nakano, M., Taguchi, R., Kikushige, Y*., Isobe, T., Miyawaki, K., Mizuno, S., Tsuruta, N., Hanamura, F., Yamaguchi, K., Yamauchi, T., Ariyama, H., Kusaba, H., Nakamura, M., Maeda, T., Kuo, C.J., Baba, E*. & Akashi, K. , Cancer Science, 2023.08. |
| 6. |
Nakashima, K., Kunisaki, Y., Hosokawa, K., Gotoh, K., Yao, H., Yuta, R., Semba, Y., Nogami, J., Kikushige, Y., Stumpf, P.S., MacArthur, B.D., Kang, D., Akashi, K., Ohga, S. & Arai, F. , POT1a deficiency in mesenchymal niches perturbs B-lymphopoiesis., Commun Biol, 2023.10. |
| 7. |
Irifune, H., Kochi, Y., Miyamoto, T., Sakoda, T., Kato, K., Kunisaki, Y., Akashi, K. & Kikushige, Y. , GPAM mediated lysophosphatidic acid synthesis regulates mitochondrial dynamics in acute myeloid leukemia, Cancer Sciences, 2023.04. |
| 8. |
Sakoda, T., Kikushige, Y*., Miyamoto, T., Irifune, H., Harada, T., Hatakeyama, K., Kunisaki, Y., Kato, K. & Akashi, K. , TIM-3 signaling hijacks the canonical Wnt/beta-catenin pathway to maintain cancer stemness in acute myeloid leukemia, Blood Advances, 10.1182/bloodadvances.2022008405, 2023.01. |
| 9. |
Kikushige, Y., Miyamoto, T., Kochi, Y., Semba, Y., Ohishi, M., Irifune, H., Hatakeyama, K., Kunisaki, Y., Sugio, T., Sakoda, T., Miyawaki, K., Kato, K., Soga, T. & Akashi, K., Human acute leukemia utilizes branched-chain amino acid catabolism to maintain stemness through regulating PRC2 function, Blood Advances, 10.1182/bloodadvances.2022008242, 2022.07. |
| 10. |
Hatakeyama, K., Hieda, M., Semba, Y., Moriyama, S., Wang, Y., Maeda, T., Kato, K., Miyamoto, T., Akashi, K. & Kikushige, Y*, TET2 Clonal Hematopoiesis Is Associated With Anthracycline-Induced Cardiotoxicity in Patients With Lymphoma, JACC CardioOncol, 10.1016/j.jaccao.2022.01.098, 2022.10. |
| 11. |
Mori, Y., Harada, T., Yoshimoto, G., Shima, T., Numata, A., Jinnouchi, F., Yamauchi, T., Kikushige, Y., Kunisaki, Y., Kato, K., Takenaka, K., Akashi, K. & Miyamoto, T., Risk factors for late cytomegalovirus infection after completing letermovir prophylaxis, INTERNATIONAL JOURNAL OF HEMATOLOGY, 10.1007/s12185-022-03348-2, 116, 2, 258-265, 2022.08. |
| 12. |
Sugio, T., Baba, S., Mori, Y., Yoshimoto, G., Kamesaki, K., Takashima, S., Urata, S., Shima, T., Miyawaki, K., Kikushige, Y., Kunisaki, Y., Numata, A., Takenaka, K., Iawasaki, H., Miyamoto, T., Ishigami, K., Akashi, K. & Kato, K, Prognostic value of pre-transplantation total metabolic tumor volume on (18)fluoro-2-deoxy-d-glucose positron emission tomography-computed tomography in relapsed and refractory aggressive lymphoma, INTERNATIONAL JOURNAL OF HEMATOLOGY, 10.1007/s12185-022-03394-w, 116, 4, 603-611, 2022.10. |
| 13. |
Taniguchi, S., Utsumi, S., Kochi, Y., Taya, Y., Mori, Y., Semba, Y.I., Sugio, T., Miyawaki, K., Kikushige, Y., Kunisaki, Y., Yoshimoto, G., Numata, A., Kato, K., Uchida, N., Maeda, T., Miyamoto, T., Taniguchi, S. & Akashi, K, Successful pseudo-autologous stem cell transplantation for donor-derived Burkitt lymphoma occurring 9 years after allogeneic transplantation, INTERNATIONAL JOURNAL OF HEMATOLOGY, 10.1007/s12185-022-03458-x, 117, 2, 287-292, 2023.02. |
| 14. |
Nakao, F., Setoguchi, K., Semba, Y., Yamauchi, T., Nogami, J., Sasaki, K., Imanaga, H., Terasaki, T., Miyazaki, M., Hirabayashi, S., Miyawaki, K., Kikushige, Y., Masuda, T., Akashi, K. & Maeda, T., Targeting a mitochondrial E3 ubiquitin ligase complex to overcome AML cell-intrinsic Venetoclax resistance, Leukemia, 10.1038/s41375-023-01879-z, 2023.01. |
| 15. |
Yoshikane Kikushige, TIM-3 in normal and malignant hematopoiesis: Structure, function, and signaling pathways. , Cancer Science, 2021.06. |
| 16. |
Miyawaki, K., Kato, K., Sugio, T., Sasaki, K., Miyoshi, H., Semba, Y., Kikushige, Y., Mori, Y., Kunisaki, Y., Iwasaki, H., Miyamoto, T., Kuo, F.C., Aster, J.C., Ohshima, K., Maeda, T. & Akashi, K., A germinal center-associated microenvironmental signature reflects malignant phenotype and outcome of DLBCL, Blood Advances, 2021.12. |
| 17. |
Ito, M., Nakano, M., Ariyama, H., Yamaguchi, K., Tanaka, R., Semba, Y., Sugio, T., Miyawaki, K., Kikushige, Y., Mizuno, S., Isobe, T., Tanoue, K., Taguchi, R., Ueno, S., Kawano, T., Murata, M., Baba, E. & Akashi, K., Macrophages are primed to transdifferentiate into fibroblasts in malignant ascites and pleural effusions., Cancer Lett,, 2022.03. |
| 18. |
Yoshikane Kikushige, Pathogenesis of chronic lymphocytic leukemia and the development of novel therapeutic strategies., J Clin Exp Hematop. , 60, 146-158, 2020.12. |
| 19. |
Taro Tochigi, Toshihiro Miyamoto, Kiwamu Hatakeyama, Teppei Sakoda, Daisuke Ishihara, Hidetoshi Irifune, Takahiro Shima, Koji Kato,
Takahiro Maeda, Takumi Ito, Hiroshi Handa, Koichi Akashi, and Yoshikane Kikushige, Aromatase is a novel neosubstrate of cereblon responsible for immunomodulatory drug–induced thrombocytopenia, Blood, 2020.06. |
| 20. |
Junichiro Yuda , Jun Odawara , Mariko Minami , Tsuyoshi Muta , Kentaro Kohno , Kazuki Tanimoto , Tetsuya Eto , Takahiro Shima , Yoshikane Kikushige , Koji Kato , Katsuto Takenaka , Hiromi Iwasaki , Yosuke Minami , Yasuyuki Ohkawa , Koichi Akashi , Toshihiro Miyamoto, TKIs Induce Alternative Spliced BCR-ABL Ins35bp Variant via Inhibition of RNA Polymerase Ⅱ on Genomic BCR-ABL, CANCER SCIENCE, 10.1111/cas.14424., 2020.04. |
| 21. |
Fumiaki Jinnouchi, Takuji Yamauchi, Ayano Yurino, Takuya Nunomura, Michitaka Nakano, Chika Iwamoto, Teppei Obara, Kohta Miyawaki, Yoshikane Kikushige, Koji Kato, Takahiro Maeda, Toshihiro Miyamoto, Eishi Baba, Koichi Akashi, Katsuto Takenaka, A human SIRPA knock-in xenograft mouse model to study human hematopoietic and cancer stem cells, Blood, 2020.03. |
| 22. |
Kazuhiko Higashioka, Yoshikane Kikushige, Masahiro Ayano, Yasutaka Kimoto, Hiroki Mitoma, Makoto Kikukawa, Mitsuteru Akahoshi, Yojiro Arinobu, Takahiko Horiuchi, Koichi Akashi, Hiroaki Niiro, Generation of a novel CD30 + B cell subset producing GM-CSF and its possible link to the pathogenesis of systemic sclerosis, Clinical & Experimental Immunology, 10.1111/cei.13477, 201, 3, 233-243, 2020.09. |
| 23. |
Yoshikane Kikushige, Pathophysiology of chronic lymphocytic leukemia and human B1 cell development, International journal of hematology, 10.1007/s12185-019-02788-7, 111, 5, 634-641, 2020.05, Chronic lymphocytic leukemia (CLL), the most frequent type of leukemia in adults, is a lymphoproliferative disease characterized by the clonal expansion of mature CD5+ B cells in peripheral blood, bone marrow, and secondary lymphoid tissues. Over the past decade, substantial advances have been made in understanding the pathogenesis of CLL, including the identification of recurrent mutations, and clarification of clonal architectures, transcriptome analyses, and the multistep leukemogenic process. The biology of CLL is now better understood. The present review focuses on recent insights into CLL leukemogenesis, emphasizing the role of genetic lesions, and the multistep process initiating from very immature hematopoietic stem cells. Finally, we also review progress in the study of human B1 B cells, the putative normal counterparts of CLL cells.. |
| 24. |
Michitaka Nakano, Yoshikane Kikushige, Kohta Miyawaki, Yuya Kunisaki, Shinichi Mizuno, Katsuto Takenaka, Shingo Tamura, Yuta Okumura, Mamoru Ito, Hiroshi Ariyama, Hitoshi Kusaba, Masafumi Nakamura, Takahiro Maeda, Eishi Baba, Koichi Akashi, Dedifferentiation process driven by TGF-beta signaling enhances stem cell properties in human colorectal cancer, Oncogene, 10.1038/s41388-018-0480-0, 38, 6, 780-793, 2019.02, Cancer stem cells (CSCs) possess the capacity for self-renewal and the potential to differentiate into non-CSCs. The recent discoveries of dynamic equilibrium between CSCs and non-CSCs revealed the significance of acquiring CSC-like properties in non-CSCs as an important process in progression of cancer. The mechanism underlying acquisition of CSC-like properties has mainly been investigated in the context of epithelial–mesenchymal transition. Here, we demonstrate the dedifferentiation process may be an alternative mechanism in acquisition of CSC-like properties in human colorectal cancer cells. By exploring the single-cell gene expression analysis of organoids developed from CD44 + CSCs, we identified TWIST1 as a key molecule for maintaining the undifferentiated state of cancer cells. Consistent with the finding, we found that TGF-beta signaling pathway, a regulator of TWIST1, was specifically activated in the undifferentiated CD44 + CSCs in human colorectal cancer using microarray-based gene expression analysis and quantitative pathology imaging system. Furthermore, we showed that external stimulation with TGF-beta and the induction of TWIST1 converted CD44 − non-CSCs into the undifferentiated CD44 + CSCs, leading to the significant increment of CSCs in xenograft models. This study strongly suggests dedifferentiation driven by TGF-beta signaling enhances stem cell properties in human colorectal cancer.. |
| 25. |
Michitaka Nakano, Yoshikane Kikushige, Kohta Miyawaki, Yuya Kunisaki, Shinichi Mizuno, Katsuto Takenaka, Shingo Tamura, Yuta Okumura, Mamoru Ito, Hiroshi Ariyama, Hitoshi Kusaba, Masafumi Nakamura, Takahiro Maeda, Eishi Baba, Koichi Akashi, Dedifferentiation process driven by TGF-beta signaling enhances stem cell properties in human colorectal cancer, Oncogene, 10.1038/s41388-018-0480-0, 38, 6, 780-793, 2019.02, Cancer stem cells (CSCs) possess the capacity for self-renewal and the potential to differentiate into non-CSCs. The recent discoveries of dynamic equilibrium between CSCs and non-CSCs revealed the significance of acquiring CSC-like properties in non-CSCs as an important process in progression of cancer. The mechanism underlying acquisition of CSC-like properties has mainly been investigated in the context of epithelial–mesenchymal transition. Here, we demonstrate the dedifferentiation process may be an alternative mechanism in acquisition of CSC-like properties in human colorectal cancer cells. By exploring the single-cell gene expression analysis of organoids developed from CD44 + CSCs, we identified TWIST1 as a key molecule for maintaining the undifferentiated state of cancer cells. Consistent with the finding, we found that TGF-beta signaling pathway, a regulator of TWIST1, was specifically activated in the undifferentiated CD44 + CSCs in human colorectal cancer using microarray-based gene expression analysis and quantitative pathology imaging system. Furthermore, we showed that external stimulation with TGF-beta and the induction of TWIST1 converted CD44 − non-CSCs into the undifferentiated CD44 + CSCs, leading to the significant increment of CSCs in xenograft models. This study strongly suggests dedifferentiation driven by TGF-beta signaling enhances stem cell properties in human colorectal cancer.. |
| 26. |
Tatsushi Kodama, Yu Kochi, Waka Nakai, Hideaki Mizuno, Takeshi Baba, Kiyoshi Habu, Noriaki Sawada, Hiroyuki Tsunoda, Takahiro Shima, Kohta Miyawaki, Yoshikane Kikushige, Yasuo Mori, Toshihiro Miyamoto, Takahiro Maeda, Koichi Akashi, Anti-GPRC5D/CD3 bispecific T-cell-redirecting antibody for the treatment of multiple myeloma, Molecular Cancer Therapeutics, 10.1158/1535-7163.MCT-18-1216, 18, 9, 1555-1564, 2019.01, Although treatment advances over recent decades have significantly improved survival of patients with multiple myeloma, there is still an unmet medical need for more effective treatments. In this study, we identified G-protein-coupled receptor family C group 5 member D (GPRC5D) expression on the surface of malignant cells involved in multiple myeloma, but except for plasma cells and B cells, not at appreciable levels on normal hematopoietic cells and bone marrow progenitors, including hematopoietic stem cells. In addition, we constructed IgG-based anti-GPRC5D/CD3 bispecific T-cell-redirecting antibodies (GPRC5D TRAB), which suppressed the tumor growth of GPRC5D-positive myeloma cells through the activation of T cells in vitro and in vivo in xenograft models. Collectively, these findings suggest that GPRC5D is an antigen specific to multiple myeloma and a potential target of TRAB therapy.. |
| 27. |
Tatsushi Kodama, Yu Kochi, Waka Nakai, Hideaki Mizuno, Takeshi Baba, Kiyoshi Habu, Noriaki Sawada, Hiroyuki Tsunoda, Takahiro Shima, Kohta Miyawaki, Yoshikane Kikushige, Yasuo Mori, Toshihiro Miyamoto, Takahiro Maeda, Koichi Akashi, Anti-GPRC5D/CD3 bispecific T-cell-redirecting antibody for the treatment of multiple myeloma, Molecular Cancer Therapeutics, 10.1158/1535-7163.MCT-18-1216, 18, 9, 1555-1564, 2019.01, Although treatment advances over recent decades have significantly improved survival of patients with multiple myeloma, there is still an unmet medical need for more effective treatments. In this study, we identified G-protein-coupled receptor family C group 5 member D (GPRC5D) expression on the surface of malignant cells involved in multiple myeloma, but except for plasma cells and B cells, not at appreciable levels on normal hematopoietic cells and bone marrow progenitors, including hematopoietic stem cells. In addition, we constructed IgG-based anti-GPRC5D/CD3 bispecific T-cell-redirecting antibodies (GPRC5D TRAB), which suppressed the tumor growth of GPRC5D-positive myeloma cells through the activation of T cells in vitro and in vivo in xenograft models. Collectively, these findings suggest that GPRC5D is an antigen specific to multiple myeloma and a potential target of TRAB therapy.. |
| 28. |
Goichi Yoshimoto, Yasuo Mori, Koji Kato, Takahiro Shima, Kohta Miyawaki, Yoshikane Kikushige, Kenjiro Kamezaki, Akihiko Numata, Takahiro Maeda, Katsuto Takenaka, Hiromi Iwasaki, Takanori Teshima, Koichi Akashi, Toshihiro Miyamoto, Human Herpes Virus-6–Associated Encephalitis/Myelitis Mimicking Calcineurin Inhibitor–Induced Pain Syndrome in Allogeneic Stem Cell Transplantation Recipients, Biology of Blood and Marrow Transplantation, 10.1016/j.bbmt.2018.07.017, 24, 12, 2540-2548, 2018.12, Human herpes virus-6 (HHV6)-associated myelitis and calcineurin inhibitor–induced pain syndrome (CIPS) are serious complications of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Because these 2 complications cause similar sensory nerve–related symptoms, such as paresthesia, pruritus, and severe pain occurring around the engraftment, it can be difficult to differentially diagnose the 2 conditions. We retrospectively analyzed 435 recipients to distinguish clinical symptoms of these 2 complications. Twenty-four patients (5.5%) developed HHV6-associated encephalitis/myelitis; of these, 11 (2.5%) presented only with myelitis-related symptoms (HHV6-associated myelitis), which was confirmed by the detection of HHV6 DNA, and 8 (1.8%) had CIPS, with undetected HHV6 DNA. All patients with HHV6-associated myelitis or CIPS exhibited similar sensory nerve–related symptoms. Diagnostic images did not provide definite evidence specific for each disease. Symptoms of all patients with CIPS improved after switching to another immunosuppressant. Overall survival rate at 2 years for patients with HHV6-associated encephalitis/myelitis was significantly lower than that of CIPS (13.1% versus 29.2%; P =.049) or that of patients without HHV6-associated encephalitis/myelitis or CIPS (42.4%; P =.036), whereas there was no significant difference among the latter 2 groups (P =.889). The development of HHV6-associated encephalitis/myelitis but not CIPS was significantly associated with poor prognosis. Thus, transplant physicians should be aware that sensory nerve–related symptoms indicate early manifestations that might be correlated with reactivation of HHV6 or CIPS. Therefore, identification of HHV6 DNA is crucial for making a differential diagnosis and immediately starting appropriate treatments for each complication.. |
| 29. |
Goichi Yoshimoto, Yasuo Mori, Koji Kato, Takahiro Shima, Kohta Miyawaki, Yoshikane Kikushige, Kenjiro Kamezaki, Akihiko Numata, Takahiro Maeda, Katsuto Takenaka, Hiromi Iwasaki, Takanori Teshima, Koichi Akashi, Toshihiro Miyamoto, Human Herpes Virus-6–Associated Encephalitis/Myelitis Mimicking Calcineurin Inhibitor–Induced Pain Syndrome in Allogeneic Stem Cell Transplantation Recipients, Biology of Blood and Marrow Transplantation, 10.1016/j.bbmt.2018.07.017, 24, 12, 2540-2548, 2018.12, Human herpes virus-6 (HHV6)-associated myelitis and calcineurin inhibitor–induced pain syndrome (CIPS) are serious complications of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Because these 2 complications cause similar sensory nerve–related symptoms, such as paresthesia, pruritus, and severe pain occurring around the engraftment, it can be difficult to differentially diagnose the 2 conditions. We retrospectively analyzed 435 recipients to distinguish clinical symptoms of these 2 complications. Twenty-four patients (5.5%) developed HHV6-associated encephalitis/myelitis; of these, 11 (2.5%) presented only with myelitis-related symptoms (HHV6-associated myelitis), which was confirmed by the detection of HHV6 DNA, and 8 (1.8%) had CIPS, with undetected HHV6 DNA. All patients with HHV6-associated myelitis or CIPS exhibited similar sensory nerve–related symptoms. Diagnostic images did not provide definite evidence specific for each disease. Symptoms of all patients with CIPS improved after switching to another immunosuppressant. Overall survival rate at 2 years for patients with HHV6-associated encephalitis/myelitis was significantly lower than that of CIPS (13.1% versus 29.2%; P =.049) or that of patients without HHV6-associated encephalitis/myelitis or CIPS (42.4%; P =.036), whereas there was no significant difference among the latter 2 groups (P =.889). The development of HHV6-associated encephalitis/myelitis but not CIPS was significantly associated with poor prognosis. Thus, transplant physicians should be aware that sensory nerve–related symptoms indicate early manifestations that might be correlated with reactivation of HHV6 or CIPS. Therefore, identification of HHV6 DNA is crucial for making a differential diagnosis and immediately starting appropriate treatments for each complication.. |
| 30. |
Shingo Tamura, Taichi Isobe, Hiroshi Ariyama, Michitaka Nakano, Yoshikane Kikushige, Shigeo Takaishi, Hitoshi Kusaba, Katsuto Takenaka, Takashi Ueki, Masafumi Nakamura, Koichi Akashi, Eishi Baba, E-cadherin regulates proliferation of colorectal cancer stem cells through NANOG, Oncology reports, 10.3892/or.2018.6464, 40, 2, 693-703, 2018.08, Cancer stem cells (CSCs) possess a self-renewal ability and display tumorigenic potential in immunodeficient mice. Colorectal CSCs are thought to be a uniform population and no functionally distinct subpopulations have been identified. Because E-cadherin is an essential molecule for self-renewal of embryonic stem cells, we examined E-cadherin expression, which may play a role in maintaining the properties of CSCs, in EpCAMhigh/CD44+ colorectal CSCs from human primary colorectal cancers. We obtained 18 surgical specimens of human primary colorectal cancer. CD44, EpCAM, and E-cadherin expression were analyzed by fluorescence-activated cell sorting. Sorted EpCAMhigh/CD44+ colorectal CSCs were injected into immunodeficient mice to estimate the tumorigenic potential. Genetic profiles were analyzed by cDNA microarray. Notably, colorectal CSCs could be divided into two populations based on the E-cadherin expression status, and they exhibited different pathological characteristics. Compared to E-cadherin-negative colorectal CSCs, E-cadherin-positive (EC+) colorectal CSCs demonstrated higher tumor growth potential in vivo. EC+ colorectal CSCs revealed a higher expression of the pluripotency factor NANOG, which contributed to the higher tumor growth potential of EC+ colorectal CSCs through control of cyclin D1 expression. These findings are the first demonstration of functionally distinct subpopulations of colorectal CSCs in human clinical samples.. |
| 31. |
Shingo Tamura, Taichi Isobe, Hiroshi Ariyama, Michitaka Nakano, Yoshikane Kikushige, Shigeo Takaishi, Hitoshi Kusaba, Katsuto Takenaka, Takashi Ueki, Masafumi Nakamura, Koichi Akashi, Eishi Baba, E-cadherin regulates proliferation of colorectal cancer stem cells through NANOG, Oncology reports, 10.3892/or.2018.6464, 40, 2, 693-703, 2018.08, Cancer stem cells (CSCs) possess a self-renewal ability and display tumorigenic potential in immunodeficient mice. Colorectal CSCs are thought to be a uniform population and no functionally distinct subpopulations have been identified. Because E-cadherin is an essential molecule for self-renewal of embryonic stem cells, we examined E-cadherin expression, which may play a role in maintaining the properties of CSCs, in EpCAMhigh/CD44+ colorectal CSCs from human primary colorectal cancers. We obtained 18 surgical specimens of human primary colorectal cancer. CD44, EpCAM, and E-cadherin expression were analyzed by fluorescence-activated cell sorting. Sorted EpCAMhigh/CD44+ colorectal CSCs were injected into immunodeficient mice to estimate the tumorigenic potential. Genetic profiles were analyzed by cDNA microarray. Notably, colorectal CSCs could be divided into two populations based on the E-cadherin expression status, and they exhibited different pathological characteristics. Compared to E-cadherin-negative colorectal CSCs, E-cadherin-positive (EC+) colorectal CSCs demonstrated higher tumor growth potential in vivo. EC+ colorectal CSCs revealed a higher expression of the pluripotency factor NANOG, which contributed to the higher tumor growth potential of EC+ colorectal CSCs through control of cyclin D1 expression. These findings are the first demonstration of functionally distinct subpopulations of colorectal CSCs in human clinical samples.. |
| 32. |
Kohta Miyawaki, Hiromi Iwasaki, Takashi Jiromaru, Hirotake Kusumoto, Ayano Yurino, Takeshi Sugio, Yasufumi Uehara, Jun Odawara, Shinya Daitoku, Yuya Kunisaki, Yasuo Mori, Yojiro Arinobu, Hirofumi Tsuzuki, Yoshikane Kikushige, Tadafumi Iino, Koji Kato, Katsuto Takenaka, Toshihiro Miyamoto, Takahiro Maeda, Koichi Akashi, Identification of unipotent megakaryocyte progenitors in human hematopoiesis, Blood, 10.1182/blood-2016-09-741611, 129, 25, 3332-3343, 2017.06, The developmental pathway for human megakaryocytes remains unclear, and the definition of pure unipotent megakaryocyte progenitor is still controversial. Using single-cell transcriptome analysis, we have identified a cluster of cells within immature hematopoietic stem- and progenitor-cell populations that specifically expresses genes related to the megakaryocyte lineage. We used CD41 as a positive marker to identify these cells within the CD34+CD38+IL-3RαdimCD45RA- common myeloid progenitor (CMP) population. These cells lacked erythroid and granulocyte-macrophage potential but exhibited robust differentiation into the megakaryocyte lineage at a high frequency, both in vivo and in vitro. The efficiency and expansion potential of these cells exceeded those of conventional bipotent megakaryocyte/erythrocyte progenitors. Accordingly, the CD41+ CMP was defined as a unipotent megakaryocyte progenitor (MegP) that is likely to represent the major pathway for human megakaryopoiesis, independent of canonical megakaryocyte-erythroid lineage bifurcation. In the bone marrow of patients with essential thrombocythemia, the MegP population was significantly expanded in the context of a high burden of Janus kinase 2 mutations. Thus, the prospectively isolatable and functionally homogeneous human MegP will be useful for the elucidation of the mechanisms underlying normal and malignant human hematopoiesis. (Blood. 2017;129(25): 3332-3343).. |
| 33. |
Taro Tochigi, Takatoshi Aoki, Yoshikane Kikushige, Tomohiko Kamimura, Yoshikiyo Ito, Takahiro Shima, Takuji Yamauchi, Yasuo Mori, Goichi Yoshimoto, Kenjiro Kamezaki, Koji Kato, Katsuto Takenaka, Hiromi Iwasaki, Koichi Akashi, Toshihiro Miyamoto, Mobilization of human immature hematopoietic progenitors through combinatory use of bortezomib and immunomodulatory drugs, International journal of hematology, 10.1007/s12185-016-2148-2, 105, 4, 423-432, 2017.04, Combination use of the proteasome inhibitor bortezomib and the immunomodulatory drugs lenalidomide or thalidomide has provided superior outcomes in multiple myeloma over their single use; however, these combinations can produce significant toxicities. Unexpectedly, we found a small but significant increase in the population of immature granulocytes and erythrocytes/megakaryocytes in peripheral blood in 16 of 22 patients (73%) treated with dexamethasone in combination with bortezomib and immunomodulatory drugs (triplet), but not in any of 25 patients treated with either bortezomib or immunomodulatory drugs with dexamethasone (doublet). These immature cells gradually increased to a peak level (mean 2.6% per white blood cells) with triplet therapy, and disappeared immediately after therapy cessation. The numbers of circulating CD34+ cells and colony-forming cells derived from peripheral blood mononuclear cells increased after triplet therapy compared with those in patients treated by either bortezomib or immunomodulatory drugs plus dexamethasone. Furthermore, triplet regimen downregulated the expression of CXCR4, a chemokine receptor essential for bone marrow retention, on CD34+ cells, suggesting an unexpected effect on normal hematopoietic stem/progenitor cells through the reduced interaction with the bone marrow microenvironment. Our observations suggest that combination use should be carefully evaluated to exert synergistic anti-myeloma effects while avoiding unexpected adverse events.. |
| 34. |
Ayano Yurino, Katsuto Takenaka, Takuji Yamauchi, Takuya Nunomura, Yasufumi Uehara, Fumiaki Jinnouchi, Kohta Miyawaki, Yoshikane Kikushige, Koji Kato, Toshihiro Miyamoto, Hiromi Iwasaki, Yuya Kunisaki, Koichi Akashi, Enhanced Reconstitution of Human Erythropoiesis and Thrombopoiesis in an Immunodeficient Mouse Model with KitWv Mutations, Stem Cell Reports, 10.1016/j.stemcr.2016.07.002, 7, 3, 425-438, 2016.09, In human-to-mouse xenograft models, reconstitution of human hematopoiesis is usually B-lymphoid dominant. Here we show that the introduction of homozygous KitWv mutations into C57BL/6.Rag2nullIl2rgnull mice with NOD-Sirpa (BRGS) strongly promoted human multi-lineage reconstitution. After xenotransplantation of human CD34+CD38− cord blood cells, these newly generated C57BL/6.Rag2nullIl2rgnullNOD-Sirpa KitWv/Wv (BRGSKWv/Wv) mice showed significantly higher levels of human cell chimerism and long-term multi-lineage reconstitution compared with BRGS mice. Strikingly, this mouse displayed a robust reconstitution of human erythropoiesis and thrombopoiesis with terminal maturation in the bone marrow. Furthermore, depletion of host macrophages by clodronate administration resulted in the presence of human erythrocytes and platelets in the circulation. Thus, attenuation of mouse KIT signaling greatly enhances the multi-lineage differentiation of human hematopoietic stem and progenitor cells (HSPCs) in mouse bone marrow, presumably by outcompeting mouse HSPCs to occupy suitable microenvironments. The BRGSKWv/Wv mouse model is a useful tool to study human multi-lineage hematopoiesis.. |
| 35. |
Yoshikane Kikushige, A TIM-3/galectin-9 autocrine stimulatory loop drives self-renewal of human myeloid leukemia stem cells and leukemia progression, [Rinshō ketsueki] The Japanese journal of clinical hematology, 10.11406/rinketsu.57.412, 57, 4, 412-416, 2016.04, Acute myeloid leukemia (AML) originates from self-renewing leukemic stem cells (LSCs), an ultimate therapeutic target for AML. We previously reported that the T-cell immunoglobulin mucin-3 (TIM-3) is expressed on the LCS surface in most types of AML. Since only the TIM-3(+), i.e. not the TIM-3(-), fraction of human AML cells can reconstitute human AML in immunodeficient mice, we hypothesized that the TIM-3 has an essential function in maintaining AML LSCs. Herein, we show that TIM-3 and its ligand, galectin-9 (Gal-9), constitute an autocrine loop critical for human AML LSC development. Serum Gal-9 was significantly elevated in primary AML patients and in mice xenografted with human AML. Neutralization of Gal-9 inhibited xenogeneic reconstitution of human AML, as well as Gal-9 ligation of TIM-3 co-activated NF-κB and β-catenin signaling, suggesting that TIM-3 signaling is necessary for LSC self-renewal. Interestingly, identical changes were found to be involved in the progressive transformation of a variety of pre-leukemic disorders into myeloid leukemia. Thus, molecules constituting the TIM-3/Gal-9 autocrine loop are potential therapeutic targets applicable to most types of myeloid leukemia.. |
| 36. |
Yoshikane Kikushige, Toshihiro Miyamoto, Junichiro Yuda, Siamak Jabbarzadeh-Tabrizi, Takahiro Shima, Shin Ichiro Takayanagi, Hiroaki Niiro, Ayano Yurino, Kohta Miyawaki, Katsuto Takenaka, Hiromi Iwasaki, Koichi Akashi, A TIM-3/Gal-9 Autocrine Stimulatory Loop Drives Self-Renewal of Human Myeloid Leukemia Stem Cells and Leukemic Progression, Cell stem cell, 10.1016/j.stem.2015.07.011, 17, 3, 341-352, 2015.09, Signaling mechanisms underlying self-renewal of leukemic stem cells (LSCs) are poorly understood, and identifying pathways specifically active in LSCs could provide opportunities for therapeutic intervention. T-cell immunoglobin mucin-3 (TIM-3) is expressed on the surface of LSCs in many types of human acute myeloid leukemia (AML), but not on hematopoietic stem cells (HSCs). Here, we show that TIM-3 and its ligand, galectin-9 (Gal-9), constitute an autocrine loop critical for LSC self-renewal and development of human AML. Serum Gal-9 levels were significantly elevated in AML patients and in mice xenografted with primary human AML samples, and neutralization of Gal-9 inhibited xenogeneic reconstitution of human AML. Gal-9-mediated stimulation of TIM-3 co-activated NF-κB and β-catenin signaling, pathways known to promote LSC self-renewal. These changes were further associated with leukemic transformation of a variety of pre-leukemic disorders and together highlight that targeting the TIM-3/Gal-9 autocrine loop could be a useful strategy for treating myeloid leukemias.. |
| 37. |
Yoshikane Kikushige, Molecular targeted therapy for leukemic stem cells, Nihon rinsho. Japanese journal of clinical medicine, 73, 5, 811-815, 2015.05, Acute myelogenous leukemia (AML) originates from self-renewing leukemic stem cells (LSCs), an ultimate therapeutic target for AML. LSCs play a central role in the propagation of leukemia through their unique stem cell like properties, and LSCs share the many functional molecules with their normal counterpart hematopoietic stem cells (HSCs). For the establishment of LSCs-specific therapeutic approaches, it is quite important to understand the biological differences between LSCs and HSCs. Recent, studies have succeeded in clarifying these biological differences. In this review, I would like to introduce the biological significance of LSCs and discuss the molecular targeted therapy against LSCs.. |
| 38. |
Kohta Miyawaki, Yojiro Arinobu, Hiromi Iwasaki, Kentaro Kohno, Hirofumi Tsuzuki, Tadafumi Iino, Takahiro Shima, Yoshikane Kikushige, Katsuto Takenaka, Toshihiro Miyamoto, Koichi Akashi, CD41 marks the initial myelo-erythroid lineage specification in adult mouse hematopoiesis
Redefinition of murine common myeloid progenitor, STEM CELLS, 10.1002/stem.1906, 33, 3, 976-987, 2015.03, Previous studies have predicted that reciprocal activation of GATA-1 and PU.1 regulates myelo-erythroid versus myelo-lymphoid lineage commitment in early hematopoiesis. Such PU.1-activating myelo-lymphoid progenitors exist within the lymphoid-primed multipotent progenitor (LMPP) population at the primitive Lineage-Sca-1+c-Kit+ (LSK) stage. We here show that the counterpart of GATA-1-activating myelo-erythroid progenitor resides also at the LSK stage, expressing CD41 at a high level. Purified CD41hi LSK cells showed exceedingly strong and prolonged myelo-erythroid-restricted reconstitution, and primed myelo-erythroid gene expression with a more primitive molecular signature as compared to the original common myeloid progenitor (CMP). The CD41hi LSK cells more strongly contributed to emergent and malignant myelopoiesis than LMPPs, and produced the original CMP by downregulating Sca-1 and CD41, suggesting that they are the earliest CMPs. Thus, the hematopoietic developmental map should be revised by integrating the primary branchpoint comprised of the new, isolatable CD41hi CMP and the LMPP populations. Stem Cells 2015;33:976-987. |
| 39. |
Yoshikane Kikushige, Toshihiro Miyamoto, Pre-malignant lymphoid cells arise from hematopoietic stem/progenitor cells in chronic lymphocytic leukemia, International journal of hematology, 10.1007/s12185-015-1740-1, 102, 5, 528-535, 2015.02, Human malignancies progress through a multistep process that includes the development of critical somatic mutations over the clinical course. Recent novel findings have indicated that hematopoietic stem cells (HSCs), which have the potential to self-renew and differentiate into multilineage hematopoietic cells, are an important cellular target for the accumulation of critical somatic mutations in hematological malignancies and play a central role in myeloid malignancy development. In contrast to myeloid malignancies, mature lymphoid malignancies, such as chronic lymphocytic leukemia (CLL), are thought to originate directly from differentiated mature lymphocytes; however, recent compelling data have shown that primitive HSCs and hematopoietic progenitor cells contribute to the pathogenesis of mature lymphoid malignancies. Several representative mutations of hematological malignancies have been identified within the HSCs of CLL and lymphoma patients, indicating that the self-renewing long-lived fraction of HSCs can serve as a reservoir for the development of oncogenic events. Novel mice models have been established as human mature lymphoma models, in which specific oncogenic events target the HSCs and immature progenitor cells. These data collectively suggest that HSCs can be the cellular target involved in the accumulation of oncogenic events in the pathogenesis of mature lymphoid and myeloid malignancies.. |
| 40. |
Yoshikane Kikushige, Toshihiro Miyamoto, Identification of TIM-3 as a Leukemic Stem Cell Surface Molecule in Primary Acute Myeloid Leukemia, Oncology, 10.1159/000431062, 89, 28-32, 2015.01, Acute myeloid leukemia (AML) originates from self-renewing leukemic stem cells (LSCs), an ultimate therapeutic target in AML. Eradication of LSCs should be a critical and efficient therapeutic approach for the cure of AML. T-cell immunoglobulin mucin-3 (TIM-3) is expressed in most types of AML LSCs, but not in normal hematopoietic stem cells (HSCs); therefore, TIM-3 would be one of the promising therapeutic targets to specifically kill AML LSCs, sparing normal HSCs. In xenograft models reconstituted with human AML LSCs or human normal HSCs, an anti-human TIM-3 mouse antibody with cytotoxic activities exerts a potent anti-leukemic effect by targeting AML LSCs but does not affect normal human hematopoiesis in vivo. Here, we would like to introduce the recent studies on TIM-3 in normal and malignant hematopoiesis.. |
| 41. |
Takahiro Shima, Toshihiro Miyamoto, Yoshikane Kikushige, Junichiro Yuda, Taro Tochigi, Goichi Yoshimoto, Koji Kato, Katsuto Takenaka, Hiromi Iwasaki, Shinichi Mizuno, Noriko Goto, Koichi Akashi, The ordered acquisition of Class II and Class I mutations directs formation of human t(8;21) acute myelogenous leukemia stem cell, Experimental Hematology, 10.1016/j.exphem.2014.07.267, 42, 11, 955-965.e5, 2014.11, The cellular properties of leukemia stem cells (LSCs) are achieved at least through Class I and Class II mutations that generate signals for enhanced proliferation and impaired differentiation, respectively. Here we show that in t(8;21) acute myelogenous leukemia (AML), hematopoietic stem cells (HSCs) transform into LSCs via definitively-ordered acquisition of Class II (AML1/ETO) and then Class I (c-KIT mutant) abnormalities. Six t(8;21) AML patients with c-KIT mutants maintaining>3years of complete remission were analyzed. At diagnosis, all single LSCs had both AML1/ETO and c-KIT mutations. However, in remission, 16 out of 1,728 CD34+CD38- HSCs and 89 out of 7,187 single HSC-derived myeloerythroid colonies from these patients had AML1/ETO, whose breakpoints were identical to those found in LSCs. These cells had wild-type c-KIT, which expressed AML1/ETO at a low level, and could differentiate into mature blood cells, suggesting that they may be the persistent preleukemic stem cells. Microarray analysis suggested that mutated c-KIT signaling provides LSCs with enhanced survival and proliferation. Thus, in t(8;21) AML, the acquisition of AML1/ETO is not sufficient, and the subsequent upregulation of AML1/ETO and the additional c-KIT mutant signaling are critical steps for transformation into LSCs.. |
| 42. |
Yoshikane Kikushige, Toshihiro Miyamoto, Hematopoietic stem cell aging and chronic lymphocytic leukemia pathogenesis, International journal of hematology, 10.1007/s12185-014-1651-6, 100, 4, 335-340, 2014.10, Human malignancies develop through the multistep acquisition of critical somatic mutations during the clinical course. Regarding hematological malignancies, recent novel findings have indicated that hematopoietic stem cells (HSCs), which have the potential to self-renew and differentiate into multilineage hematopoietic cells, are an important cellular target for the accumulation of critical somatic mutations and play a central role in myeloid malignancy development. In contrast to myeloid malignancies, mature lymphoid malignancies, such as chronic lymphocytic leukemia (CLL), are considered to directly originate from differentiated mature lymphocytes; however, we previously reported that the propensity to generate clonal B cells had already been acquired at the HSC stage in CLL patients. Similarly, HSC involvement has been reported in the pathogenesis of mature T cell lymphomas. These studies indicate that, in mature lymphoid, if not all, malignancies, HSCs should be considered as the critical cellular target in the oncogenic process. The prevalence of these hematological malignancies dramatically increases with age, and the effect of aging HSCs should thus be taken into account when investigating the stepwise malignant transformation process of these age-associated malignancies.. |
| 43. |
Frederik Damm, Elena Mylonas, Adrien Cosson, Kenichi Yoshida, Véronique Della Valle, Enguerran Mouly, M'boyba Diop, Laurianne Scourzic, Yuichi Shiraishi, Kenichi Chiba, Hiroko Tanaka, Satoru Miyano, Yoshikane Kikushige, Frederick Davi, Jérôme Lambert, Daniel Gautheret, Hélène Merle-Béral, Laurent Sutton, Philippe Dessen, Eric Solary, Koichi Akashi, William Vainchenker, Thomas Mercher, Nathalie Droin, Seishi Ogawa, Florence Nguyen-Khac, Olivier A. Bernard, Acquired initiating mutations in early hematopoietic cells of CLL patients, Cancer Discovery, 10.1158/2159-8290.CD-14-0104, 4, 9, 1088-1101, 2014.09, Appropriate cancer care requires a thorough understanding of the natural history of the disease, including the cell of origin, the pattern of clonal evolution, and the functional consequences of the mutations. Using deep sequencing of flow-sorted cell populations from patients with chronic lymphocytic leukemia (CLL), we established the presence of acquired mutations in multipotent hematopoietic progenitors. Mutations affected known lymphoid oncogenes, including BRAF, NOTCH1, and SF3B1. NFKBIE and EGR2 mutations were observed at unexpectedly high frequencies, 10.7% and 8.3% of 168 advanced-stage patients, respectively. EGR2 mutations were associated with a shorter time to treatment and poor overall survival. Analyses of BRAF and EGR2 mutations suggest that they result in deregulation of B-cell receptor (BCR) intracellular signaling. Our data propose disruption of hematopoietic and early B-cell differentiation through the deregulation of pre-BCR signaling as a phenotypic outcome of CLL mutations and show that CLL develops from a pre-leukemic phase. SIGNIFICANCE: The origin and pathogenic mechanisms of CLL are not fully understood. The current work indicates that CLL develops from pre-leukemic multipotent hematopoietic progenitors carrying somatic mutations. It advocates for abnormalities in early B-cell differentiation as a phenotypic convergence of the diverse acquired mutations observed in CLL.. |
| 44. |
Junichiro Yuda, Koji Kato, Yoshikane Kikushige, Kiyofumi Ohkusu, Makiko Kiyosuke, Keiji Sakamoto, Seido Oku, Noriko Miyake, Masako Kadowaki, Tadafumi Iino, Kazuki Tanimoto, Katsuto Takenaka, Hiromi Iwasaki, Toshihiro Miyamoto, Nobuyuki Shimono, Takanori Teshima, Koichi Akashi, Successful treatment of invasive zygomycosis based on a prompt diagnosis using molecular methods in a patient with acute myelogenous leukemia, Internal Medicine, 10.2169/internalmedicine.53.1366, 53, 10, 1087-1091, 2014, Zygomycosis is a lethal and invasive mold infection that is often associated with hematological malignancies. The keys for successful treatment include making a rapid diagnosis and appropriately administering an-tifungal agents. We herein report the early diagnosis of a case of zygomycosis in a patient with acute myeloid leukemia using a deoxyribonucleic acid sequence analysis. We successfully performed allogeneic he-matopoietic stem cell transplantation with the use of high-dose liposomal amphotericin B and granulocyte transfusion.. |
| 45. |
Yoshikane Kikushige, Toshihiro Miyamoto, TIM-3 as a novel therapeutic target for eradicating acute myelogenous leukemia stem cells, International journal of hematology, 10.1007/s12185-013-1433-6, 98, 6, 627-633, 2013.12, Acute myelogenous leukemia (AML) originates from self-renewing leukemic stem cells (LSCs), which represent the ultimate therapeutic target for AML. Recent studies have identified several AML LSC-specific surface antigens as candidate targets of therapeutic molecules. T cell immunoglobulin mucin-3 (TIM-3) is expressed on LSCs in most types of AML, with the exception of acute promyelocytic leukemia, but not on normal hematopoietic stem cells (HSCs). In xenograft models reconstituted with human AML LSCs or HSCs, an anti-human TIM-3 mouse IgG2a antibody with cytotoxic activities eradicates AML LSCs in vivo, but does not affect normal human hematopoiesis. Thus, TIM-3 is a promising therapeutic target for the eradication of AML LSCs.. |
| 46. |
Tomohito Matsuo, Yukiko Noguchi, Mieko Shindo, Yoshifumi Morita, Yoshie Oda, Eiko Yoshida, Hiroko Hamada, Mine Harada, Yuichi Shiokawa, Takahiro Nishida, Ryuji Tominaga, Yoshikane Kikushige, Koichi Akashi, Jun Kudoh, Nobuyoshi Shimizu, Yuka Tanaka, Tsukuru Umemura, Taketoshi Taniguchi, Akihiko Yoshimura, Takashi Kobayashi, Masao Mitsuyama, Hironori Kurisaki, Hitoshi Katsuta, Seiho Nagafuchi, Regulation of human autoimmune regulator (AIRE) gene translation by miR-220b, Gene, 10.1016/j.gene.2013.08.015, 530, 1, 19-25, 2013.11, Although mutations of autoimmune regulator (AIRE) gene are responsible for autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), presenting a wide spectrum of many characteristic and non-characteristic clinical features, some patients lack AIRE gene mutations. Therefore, something other than a mutation, such as dysregulation of AIRE gene, may be a causal factor for APECED or its related diseases. However, regulatory mechanisms for AIRE gene expression and/or translation have still remained elusive. We found that IL-2-stimulated CD4+ T (IL-2T) cells showed a high expression of AIRE gene, but very low AIRE protein production, while Epstein-Barr virus-transformed B (EBV-B) cells express both AIRE gene and AIRE protein. By using microarray analysis, we could identify miR-220b as a possible regulatory mechanism for AIRE gene translation in IL-2T cells. Here we report that miR-220b significantly reduced the expression of AIRE protein in AIRE gene with 3'UTR region transfected 293T cells, whereas no alteration of AIRE protein production was observed in the open reading frame of AIRE gene alone transfected cells. In addition, anti-miR-220b reversed the inhibitory function of miR-220b for the expression of AIRE protein in AIRE gene with 3'UTR region transfected cells. Moreover, when AIRE gene transfected cells with mutated 3'UTR were transfected with miR-220b, no reduction of AIRE protein production was observed. Taken together, it was concluded that miR-220b inhibited the AIRE gene translation through the 3'UTR region of AIRE gene, indicating that miR-220b could serve as a regulator for human AIRE gene translation.. |
| 47. |
Takashi Nakaike, Koji Kato, Seido Oku, Masayasu Hayashi, Yoshikane Kikushige, Mika Kuroiwa, Katsuto Takenaka, Hiromi Iwasaki, Toshihiro Miyamoto, Takanori Teshima, Koichi Ohshima, Koichi Akashi, Reduced-intensity conditioning followed by cord blood transplantation in a patient with refractory folliculotropic mycosis fungoides, International journal of hematology, 10.1007/s12185-013-1410-0, 98, 4, 491-495, 2013.10, Advanced-stage mycosis fungoides (MF) has a generally poor prognosis. Allogeneic hematopoietic stem cell transplantation improves the outcome of advanced-stage MF. Recently, cord blood has been used as an alternative stem cell source; however, there are few reports of MF patients treated using cord blood transplantation. Here, we report a rare case of refractory folliculotropic MF, which was treated with reduced-intensity conditioning followed by cord blood transplantation.. |
| 48. |
Takuji Yamauchi, Katsuto Takenaka, Shingo Urata, Takahiro Shima, Yoshikane Kikushige, Takahito Tokuyama, Chika Iwamoto, Mariko Nishihara, Hiromi Iwasaki, Toshihiro Miyamoto, Nakayuki Honma, Miki Nakao, Takashi Matozaki, Koichi Akashi, Polymorphic Sirpa is the genetic determinant for NOD-based mouse lines to achieve efficient human cell engraftment, Blood, 10.1182/blood-2012-06-440354, 121, 8, 1316-1325, 2013.02, Current mouse lines efficient for human cell xenotransplantation are backcrossed into NOD mice to introduce its multiple immunodeficient phenotypes. Our positional genetic study has located the NOD-specific polymorphic Sirpa as a molecule responsible for its high xenograft efficiency: it recognizes human CD47 and the resultant signaling may cause NOD macrophages not to engulf human grafts. In the present study, we established C57BL/6.Rag2 null//2rgnull mice harboring NOD-Sirpa (BRGS). BRGS mice engrafted human hematopoiesis with an efficiency that was equal to or even better than that of the NOD.Rag1null//2rgnull strain, one of the best xenograft models. Consequently, BRGS mice are free from other NOD-related abnormalities; for example, they have normalized C5 function that enables the evaluation of complement-dependent cytotoxicity of antibodies against human grafts in the humanized mouse model. Our data show that efficient human cell engraftment found in NOD-based models is mounted solely by their polymorphic Sirpa. The simplified BRGS line should be very useful in future studies of human stem cell biology.. |
| 49. |
Takahiro Shima, Toshihiro Miyamoto, Yoshikane Kikushige, Yasuo Mori, Kenjiro Kamezaki, Ken Takase, Hideho Henzan, Akihiko Numata, Yoshikiyo Ito, Katsuto Takenaka, Hiromi Iwasaki, Tomohiko Kamimura, Tetsuya Eto, Koji Nagafuji, Takanori Teshima, Koji Kato, Koichi Akashi, Quantitation of hematogones at the time of engraftment is a useful prognostic indicator in allogeneic hematopoietic stem cell transplantation, Blood, 10.1182/blood-2012-02-409607, 121, 5, 840-848, 2013.01, Transient marrow expansion of normal B-cell precursors, termed hematogones, is occasionally observed after hematopoietic stem cell transplantation (HSCT). To understand the clinical significance of this phenomenon, we enumerated hematogones in 108 consecutive patients who received allogeneic HSCT for the treatment of hematologic malignancies, including acute myelogenous leukemia, advanced myelodysplastic syndromes, acute lymphoblastic leukemia, and non-Hodgkin lymphoma. Hematogone quantitation was performed at the time of complete donor engraftment (median day 25 and 32 in patients who received bone marrow and cord blood cell transplants, respectively). Hematogones were polyclonal B cells, and their frequencies correlated positively with blood B-cell numbers, and inversely with donors' but not recipients' age, suggesting that hematogones reflect cell-intrinsic B-cell potential of donor cells. Interestingly, patients developing hematogones that comprised > 5% of bone marrow mononuclear cells constituted a group with significantly prolonged overall survival and relapse-free survival, irrespective of their primary disease or donor cell source. In addition, patients with > 5% hematogones developed severe acute graft-versus-host diseases less frequently, which may contribute toward their improved survival. We therefore conclude that the amount of hematogones at the time of engraftment may be a useful tool in predicting the prognosis of patients treated with allogeneic HSCT.. |
| 50. |
Takuro Kuriyama, Katsuto Takenaka, Kentaro Kohno, Takuji Yamauchi, Shinya Daitoku, Goichi Yoshimoto, Yoshikane Kikushige, Junji Kishimoto, Yasunobu Abe, Naoki Harada, Toshihiro Miyamoto, Hiromi Iwasaki, Takanori Teshima, Koichi Akashi, Engulfment of hematopoietic stem cells caused by down-regulation of CD47 is critical in the pathogenesis of hemophagocytic lymphohistiocytosis, Blood, 10.1182/blood-2012-02-408864, 120, 19, 4058-4067, 2012.11, Hemophagocytic lymphohistiocytosis (HLH) is characterized by deregulated engulfment of hematopoietic stem cells (HSCs) by BM macrophages, which are activated presumably by systemic inflammatory hypercytokinemia. In the present study, we show that the pathogenesis of HLH involves impairment of the antiphagocytic system operated by an interaction between surface CD47 and signal regulatory protein α (SIRPA). In HLH patients, changes in expression levels and HLH-specific polymorphism of SIRPA were not found. In contrast, the expression of surface CD47 was down-regulated specifically in HSCs in association with exacerbation of HLH, but not in healthy subjects. The number of BM HSCs in HLH patients was reduced to approximately 20% of that of healthy controls and macrophages from normal donors aggressively engulfed HSCs purified from HLH patients, but not those from healthy controls in vitro. Furthermore, in response to inflammatory cytokines, normal HSCs, but not progenitors or mature blood cells, down-regulated CD47 sufficiently to be engulfed by macrophages. The expression of prophagocytic calreticulin was kept suppressed at the HSC stage in both HLH patients and healthy controls, even in the presence of inflammatory cytokines. These data suggest that the CD47-SIRPA antiphagocytic system plays a key role in the maintenance of HSCs and that its disruption by HSC-specific CD47 down-regulation might be critical for HLH development.. |
| 51. |
Yasuo Mori, Toshihiro Miyamoto, Kenjiro Kamezaki, Koji Kato, Yoshikane Kikushige, Shuichiro Takashima, Shingo Urata, Shinji Shimoda, Nobuyuki Shimono, Katsuto Takenaka, Hiromi Iwasaki, Koji Nagafuji, Takanori Teshima, Koichi Akashi, Low incidence of adenovirus hemorrhagic cystitis following autologous hematopoietic stem cell transplantation in the rituximab era, American Journal of Hematology, 10.1002/ajh.23247, 87, 8, 828-830, 2012.08. |
| 52. |
Chiyo Mizuochi, Stuart T. Fraser, Katia Biasch, Yuka Horio, Yoshikane Kikushige, Kenzaburo Tani, Koichi Akashi, Manuela Tavian, Daisuke Sugiyama, Intra-aortic clusters undergo endothelial to hematopoietic phenotypic transition during early embryogenesis, PloS one, 10.1371/journal.pone.0035763, 7, 4, 2012.04, Intra-aortic clusters (IACs) attach to floor of large arteries and are considered to have recently acquired hematopoietic stem cell (HSC)-potential in vertebrate early mid-gestation embryos. The formation and function of IACs is poorly understood. To address this issue, IACs were characterized by immunohistochemistry and flow cytometry in mouse embryos. Immunohistochemical analysis revealed that IACs simultaneously express the surface antigens CD31, CD34 and c-Kit. As embryos developed from 9.5 to 10.5 dpc, IACs up-regulate the hematopoietic markers CD41 and CD45 while down-regulating the endothelial surface antigen VE-cadherin/CD144, suggesting that IACs lose endothelial phenotype after 9.5 dpc. Analysis of the hematopoietic potential of IACs revealed a significant change in macrophage CFC activity from 9.5 to 10.5 dpc. To further characterize IACs, we isolated IACs based on CD45 expression. Correspondingly, the expression of hematopoietic transcription factors in the CD45(neg) fraction of IACs was significantly up-regulated. These results suggest that the transition from endothelial to hematopoietic phenotype of IACs occurs after 9.5 dpc.. |
| 53. |
Hiroaki Niiro, Siamak Jabbarzadeh-Tabrizi, Yoshikane Kikushige, Takahiro Shima, Kumiko Noda, Shun Ichiro Ota, Hirofumi Tsuzuki, Yasushi Inoue, Yojiro Arinobu, Hiromi Iwasaki, Shinji Shimoda, Eishi Baba, Hiroshi Tsukamoto, Takahiko Horiuchi, Tadayoshi Taniyama, Koichi Akashi, CIN85 is required for Cbl-mediated regulation of antigen receptor signaling in human B cells, Blood, 10.1182/blood-2011-04-351965, 119, 10, 2263-2273, 2012.03, The aberrant regulation of B-cell receptor (BCR) signaling allows unwanted B cells to persist, thereby potentially leading to autoimmunity and B-cell malignancies. Casitas B-lineage lymphoma (Cbl) proteins suppress BCR signaling; however, the molecular mechanisms that control Cbl function in human B cells remain unclear. Here, we demonstrate that CIN85 (c-Cbl interacting protein of 85 kDa) is constitutively associated with c-Cbl, Cbl-b, and B-cell linker in B cells. Experiments using CIN85-overexpressing and CIN85-knockdown B-cell lines revealed that CIN85 increased c-Cbl phosphorylation and inhibited BCR-induced calcium flux and phosphorylation of Syk and PLCγ2, whereas it did not affect BCR internalization. The Syk phosphorylation in CIN85-overexpressing and CIN85-knockdown cells was inversely correlated with the ubiquitination and degradation of Syk. Moreover, CIN85 knockdown in primary B cells enhanced BCR-induced survival and growth, and increased the expression of BcLxL, A1, cyclin D2, and myc. Following the stimulation of BCR and Toll-like receptor 9, B-cell differentiation-associated molecules were up-regulated in CIN85-knockdown cells. Together, these results suggest that CIN85 is required for Cbl-mediated regulation of BCR signaling and for downstream events such as survival, growth, and differentiation of human B cells.. |
| 54. |
Yoshikane Kikushige, Koichi Akashi, TIM-3 as a therapeutic target for malignant stem cells in acute myelogenous leukemia, Annals of the New York Academy of Sciences, 10.1111/j.1749-6632.2012.06550.x, 1266, 1, 118-123, 2012.01, Acute myeloid leukemia (AML) originates from self-renewing leukemic stem cells (LSCs), an ultimate therapeutic target for AML. Recent studies have shown that many AML LSC-specific surface antigens could be such candidates. T cell immunoglobulin mucin-3 (TIM-3) is expressed on LSCs in most types of AML, except for acute promyelocytic leukemia, but not on normal hematopoietic stem cells (HSCs). In mouse models reconstituted with human AML LSCs or human hematopoietic stem cells, a human TIM-3 mouse IgG2a antibody with complement-dependent and antibody-dependent cellular cytotoxic activities eradicates AML LSCs in vivo but does not affect normal human hematopoiesis. Thus, TIM-3 is one of the promising targets to eradicate AML LSCs.. |
| 55. |
Yoshikane Kikushige, Fumihiko Ishikawa, Toshihiro Miyamoto, Takahiro Shima, Shingo Urata, Goichi Yoshimoto, Yasuo Mori, Tadafumi Iino, Takuji Yamauchi, Tetsuya Eto, Hiroaki Niiro, Hiromi Iwasaki, Katsuto Takenaka, Koichi Akashi, Self-Renewing Hematopoietic Stem Cell Is the Primary Target in Pathogenesis of Human Chronic Lymphocytic Leukemia, Cancer Cell, 10.1016/j.ccr.2011.06.029, 20, 2, 246-259, 2011.08, We report here that in chronic lymphocytic leukemia (CLL), the propensity to generate clonal B cells has been acquired already at the hematopoietic stem cell (HSC) stage. HSCs purified from patients with CLL displayed lymphoid-lineage gene priming and produced a high number of polyclonal B cell progenitors. Strikingly, their maturation into B cells was restricted always to mono- or oligo-clones with CLL-like phenotype in xenogeneic recipients. These B cell clones were independent of the original CLL clones because they had their own immunoglobulin VDJ genes. Furthermore, they used preferentially VH genes frequently used in human CLL, presumably reflecting the role of B cell receptor signaling in clonal selection. These data suggest that HSCs can be involved in leukemogenesis even in mature lymphoid tumors.. |
| 56. |
Yoshikane Kikushige, Toshihiro Miyamoto, Koichi Akashi, [Specific surface markers of AML-leukemic stem cells]., [Rinshō ketsueki] The Japanese journal of clinical hematology, 52, 7, 531-534, 2011.07. |
| 57. |
Yoshikane Kikushige, Takahiro Shima, Shin-ichiro Takayanagi, Shingo Urata, Toshihiro Miyamoto, Hiromi Iwasaki, Katsuto Takenaka, Takanori Teshima, Toshiyuki Tanaka, Yoshimasa Inagaki, Koichi Akashi, TIM-3 is a promising target to selectively kill acute myeloid leukemia stem cells, Cell Stem Cell, 10.1016/j.stem.2010.11.014, 7, 708-717, 2010.12. |
| 58. |
Seido Oku, Katsuto Takenaka, Takuro Kuriyama, Kotaro Shide, Takashi Kumano, Yoshikane Kikushige, Shingo Urata, Takuji Yamauchi, Chika Iwamoto, Haruko K. Shimoda, Toshihiro Miyamoto, Koji Nagafuji, Junji Kishimoto, Kazuya Shimoda, Koichi Akashi, JAK2 V617F uses distinct signalling pathways to induce cell proliferation and neutrophil activation
Research paper, British Journal of Haematology, 10.1111/j.1365-2141.2010.08249.x, 150, 3, 334-344, 2010.08, Summary The acquired JAK2 V617F mutation is observed in the majority of patients with BCR-ABL1 negative chronic myeloproliferative neoplasms (MPN). BCR-ABL1 negative MPN displays myeloproliferation with an elevated leucocyte alkaline phosphatase (LAP) activity, a neutrophil activation marker. We tried to separate the downstream signalling of JAK2 V617F to stimulate myeloproliferation and LAP activity. NB4, a myeloid lineage cell line, was transduced with Jak2 V617F mutation or wild-type Jak2. We found that Jak2 V617F mutation, but not wild-type Jak2 enhanced LAP expression in NB4-derived neutrophils and proliferation of NB4 cells. JAK2 V617F induces constitutive phosphorylation of STAT3 and STAT5, and uses signalling targets such as Ras/MEK/ERK and PI3K/Akt pathways. By using MEK1/2 inhibitor U0126, PI3K inhibitor LY294002, and STAT3 or STAT5 siRNAs, JAK2 V617F was found to specifically use the STAT3 pathway to enhance LAP expression, while STAT5, Ras/MEK/ERK and PI3K/Akt, but not STAT3 pathways, were able to stimulate cell proliferation. These data strongly suggest that JAK2 V617F uses distinct signalling pathways to induce typical pathological features of MPN, such as high LAP activity and enhanced cell proliferation.. |
| 59. |
Yoshikane Kikushige, Toshihiro Miyamoto, Koichi Akashi, [Hematopoietic stem cells are primarily involved in pathogenesis of chronic lymphocytic leukemia]., [Rinsho ketsueki] The Japanese journal of clinical hematology, 51, 8, 679-684, 2010.08. |
| 60. |
Goichi Yoshimoto, Toshihiro Miyamoto, Siamak Jabbarzadeh-Tabrizi, Tadafumi Iino, Jennifer L. Rocnik, Yoshikane Kikushige, Yasuo Mori, Takahiro Shima, Hiromi Iwasaki, Katsuto Takenaka, Koji Nagafuji, Shin Ichi Mizuno, Hiroaki Niiro, Gary D. Gilliland, Koichi Akashi, FLT3-ITD up-regulates MCL-1 to promote survival of stem cells in acute myeloid leukemia via FLT3-ITD-specific STAT5 activation, Blood, 10.1182/blood-2008-12-196055, 114, 24, 5034-5043, 2009.12, Myeloid cell leukemia-1 (MCL-1) is an essential survival factor for hematopoiesis. In humans, hematopoietic stem cells (HSCs) express MCL-1 at the highest level in response to FMS-like tyrosine kinase-3 (FLT3) signaling. We here show that this FLT3-dependent stem cell maintenance system also plays a critical role in survival of leukemic stem cells (LSCs) in acute myeloid leukemia (AML). The CD34+CD38- LSC fraction expresses high levels of FLT3 as well as MCL-1, even compared with normal HSCs. Treatment with FLT3 ligand induced further MCL-1 up-regulation in LSCs in all AML cases tested. Interestingly, the group of samples expressing the highest levels of MCL-1 constituted AML with FLT3-internal tandem duplications (ITD). In FLT3-ITD AML cell lines, cells expressed a high level of MCL-1, and an inhibition of MCL-1 induced their apoptotic cell death. A tyrosine kinase inhibitor suppressed MCL-1 expression, and induced apoptosis that was reversed by the enforced MCL-1 expression. Finally, transduction of FLT3-ITD into HSCs strongly activated MCL-1 expression through its signal transducer and activator of transcription 5 (STAT5)-docking domains. This effect was completely abrogated when STAT5 activation was blocked. Thus, the acquisition of FLT3-ITD ensures LSC survival by upregulating MCL-1 via constitutive STAT5 activation that is independent of wild-type FLT3 signaling.. |
| 61. |
Siamak Jabbarzadeh Tabrizi, Hiroaki Niiro, Mariko Masui, Goichi Yoshimoto, Tadafumi Iino, Yoshikane Kikushige, Takahiro Wakasaki, Eishi Baba, Shinji Shimoda, Toshihiro Miyamoto, Toshiro Hara, Koichi Akashi, T cell leukemia/lymphoma 1 and galectin-1 regulate survival/cell death pathways in human naive and IgM+ memory B cells through altering balances in Bcl-2 family proteins, Journal of Immunology, 10.4049/jimmunol.182.3.1490, 182, 3, 1490-1499, 2009.02, BCR signaling plays a critical role in purging the self-reactive repertoire, or in rendering it anergic to establish self-tolerance in the periphery. Differences in self-reactivity between human naive and IgM + memory B cells may reflect distinct mechanisms by which BCR signaling dictates their survival and death. Here we demonstrate that BCR stimulation protected naive B cells from apoptosis with induction of prosurvival Bcl-2 family proteins, Bcl-xL and Mcl-1, whereas it rather accelerated apoptosis of IgM+ memory B cells by inducing proapoptotic BH3-only protein Bim. We found that BCR-mediated PI3K activation induced the expression of Mcl-1, whereas it inhibited Bim expression in B cells. Phosphorylation of Akt, a downstream molecule of PI3K, was more sustained in naive than IgM+ memory B cells. Abundant expression of T cell leukemia/lymphoma 1 (Tcl1), an Akt coactivator, was found in naive B cells, and enforced expression of Tcl1 induced a high level of Mcl-1 expression, resulting in prolonged B cell survival. In contrast, Galectin-1 (Gal-1) was abundantly expressed in IgM+ memory B cells, and inhibited Akt phosphorylation, leading to Bim up-regulation. Enforced expression of Gal-1 induced accelerated apoptosis in B cells. These results suggest that a unique set of molecules, Tcl1 and Gal-1, defines distinct BCR signaling cascades, dictating survival and death of human naive and IgM+ memory B cells.. |
| 62. |
Yasuo Mori, Hiromi Iwasaki, Kentaro Kohno, Goichi Yoshimoto, Yoshikane Kikushige, Aki Okeda, Naokuni Uike, Hiroaki Niiro, Katsuto Takenaka, Koji Nagafuji, Toshihiro Miyamoto, Mine Harada, Kiyoshi Takatsu, Koichi Akashi, Identification of the human eosinophil lineage-committed progenitor
Revision of phenotypic definition of the human common myeloid progenitor, Journal of Experimental Medicine, 10.1084/jem.20081756, 206, 1, 183-193, 2009.01, To establish effective therapeutic strategies for eosinophil-related disorders, it is critical to understand the developmental pathway of human eosinophils. In mouse hematopoiesis, eosinophils originate from the eosinophil lineage-committed progenitor (EoP) that has been purified downstream of the granulocyte/macrophage progenitor (GMP). We show that the EoP is also isolatable in human adult bone marrow. The previously defined human common myeloid progenitor (hCMP) population (Manz, M.G., T. Miyamoto, K. Akashi, and I.L. Weissman. 2002. Proc. Natl. Acad. Sci. USA. 99:11872-11877) was composed of the interleukin 5 receptor α chain+ (IL-5Rα +) and IL-5Rα - fractions, and the former was the hEoP. The IL- 5Rα +CD34 +CD38 +IL-3Rα +CD45RA~ hEoPs gave rise exclusively to pure eosinophil colonies but never differentiated into basophils or neutrophils. The IL-5Rα - hCMP generated the hEoP together with the hGMP or the human megakaryocyte/erythrocyte progenitor (hMEP), whereas hGMPs or hMEPs never differentiated into eosinophils. Importantly, the number of hEoPs increased up to 20% of the conventional hCMP population in the bone marrow of patients with eosinophilia, suggesting that the hEoP stage is involved in eosinophil differentiation and expansion in vivo. Accordingly, the phenotypic definition of hCMP should be revised to exclude the hEoP; an "IL-5Rα- negative" criterion should be added to define more homogenous hCMP. The newly identified hEoP is a powerful tool in studying pathogenesis of eosinophilia and could be a therapeutic target for a variety of eosinophil-related disorders.. |
| 63. |
Yoshikane Kikushige, Goichi Yoshimoto, Toshihiro Miyamoto, Tadafumi Iino, Yasuo Mori, Hiromi Iwasaki, Hiroaki Niiro, Katsuto Takenaka, Koji Nagafuji, Mine Harada, Fumihiko Ishikawa, Koichi Akashi, Human Flt3 is expressed at the hematopoietic stem cell and the granulocyte/macrophage progenitor stages to maintain cell survival, The Journal of Immunology, 180, 7358-7367, 2008.03. |
| 64. |
Yoshikane Kikushige, Goichi Yoshimoto, Toshihiro Miyamoto, Tadafumi Iino, Yasuo Mori, Hiromi Iwasaki, Hiroaki Niiro, Katsuto Takenaka, Koji Nagafuji, Mine Harada, Fumihiko Ishikawa, Koichi Akashi, Human Flt3 is expressed at the hematopoietic stem cell and the granulocyte/macrophage progenitor stages to maintain cell survival, Journal of Immunology, 10.4049/jimmunol.180.11.7358, 180, 11, 7358-7367, 2008.01, FLT3/FLK2, a member of the receptor tyrosine kinase family, plays a critical role in maintenance of hematopoietic homeostasis, and the constitutively active form of the FLT3 mutation is one of the most common genetic abnormalities in acute myelogenous leukemia. In murine hematopoiesis, Flt3 is not expressed in self-renewing hematopoietic stem cells, but its expression is restricted to the multipotent and the lymphoid progenitor stages at which cells are incapable of self-renewal. We extensively analyzed the expression of Flt3 in human (h) hematopoiesis. Strikingly, in both the bone marrow and the cord blood, the human hematopoietic stem cell population capable of long-term reconstitution in xenogcneic hosts uniformly expressed Flt3. Furthermore, human Flt3 is expressed not only in early lymphoid progenitors, but also in progenitors continuously along the granulocyte/macrophage pathway, including the common myeloid progenitor and the granulocyte/macrophage progenitor. We further found that human Flt3 signaling prevents stem and progenitors from spontaneous apoptotic cell death at least through up-regulating Mcl-1, an indispensable survival factor for hematopoiesis. Thus, the distribution of Flt3 expression is considerably different in human and mouse hematopoiesis, and human FLT3 signaling might play an important role in cell survival, especially at stem and progenitor cells that are critical cellular targets for acute myelogenous leukemia transformation.. |
| 65. |
Yayoi Matsuo, Shoichiro Takeishi, Toshihiro Miyamoto, Atsushi Nonami, Yoshikane Kikushige, Yuya Kunisaki, Kenjiro Kamezaki, Liping Tu, Hajime Hisaeda, Katsuto Takenaka, Naoki Harada, Tomohiko Kamimura, Yuju Ohno, Tetsuya Eto, Takanori Teshima, Hisashi Gondo, Mine Harada, Koji Nagafuji, Toxoplasmosis encephalitis following severe graft-vs.-host disease after allogeneic hematopoietic stem cell transplantation
17 Yr experience in Fukuoka BMT group, European Journal of Haematology, 10.1111/j.1600-0609.2007.00919.x, 79, 4, 317-321, 2007.10, Toxoplasmosis is a rare but rapidly fatal complication that can occur following hematopoietic stem cell transplantation (HSCT). Over a 17-yr period at our institutions, a definite diagnosis of toxoplasmosis was made in only two of 925 allogeneic HSCT recipients (0.22%) and none of 641 autologous HSCT recipients. These two patients received a conventional conditioning regimen followed by transplantation from an HLA-matched donor; however, they developed severe graft-vs.-host disease, which required intensive immunosuppressive therapy. Despite prophylactic treatment with trimethoprim/sulfamethoxazole, their immunosuppressive state, as indicated by a low CD4+ cell count, might have resulted in toxoplasmosis encephalitis. Rapid and non-invasive methods such as a polymerase chain reaction (PCR) test of their cerebrospinal fluid for Toxoplasma gondii and magnetic resonance imaging of the brain were useful for providing a definitive diagnosis and prompt therapy in these patients: one patient stabilized and survived after responding to treatment with pyrimethamine/sulfodiazine whereas the other died of bacterial infection. In addition, retrospective PCR analyses of the frozen stored peripheral blood samples disclosed that detection of T. gondii preceded the onset of disease, indicating routine PCR testing of peripheral blood specimens may be an early diagnostic tool. It should be noted that when patients receiving HSCT have an unexplained fever and/or neurological complications, PCR tests should be considered to avoid cerebral lesions and improve the outcome of the patients.. |
| 66. |
Yoshikane Kikushige, Ken Takase, Keiko Sata, Ken-ichi Aoki, Akihiko Numata, Toshihiro Miyamoto, Takahiro Fukuda, Hisashi Gondo, Mine Harada, Koji Nagafuji, Repeated relapses of acute myelogenous leukemia in the isolated extramedullary sites following allogeneic bone marrow transplantations, Intern Med, 46, 1011-1014, 2007.08. |
| 67. |
Kenjiro Kamezaki, Yoshikane Kikushige, Akihiko Numata, Toshihiro Miyamoto, Ken Takase, Hideho Henzan, Ken-ichi Aoki, Koji Kato, Atsushi Nonami, Tomohiko Kamimura, Fumihiko Arima, Katsuto Takenaka, Naoki Harada, Takahiro Fukuda, Shin Hayashi, Yujyu Ohno, Tetsuya Eto, Mine Harada, Koji Nagafuji, Rituximab does not compromise the mobilization and engraftment of autologous peripheral blood stem cells in diffuse-large B-cell lymphoma, Bone Marrow Transplant, 39, 523-527, 2007.08. |
| 68. |
Koji Nagafuji, Atsushi Nonami, Takashi Kumano, Yoshikane Kikushige, Goichi Yoshimoto, Katsuto Takenaka, Kazuya Shimoda, Shouichi Ohga, Masaki Yasukawa, Hisanori Horiuchi, Eiichi Ishii, Mine Harada, Perforin gene mutations in adult-onset hemophagocytic lymphohistiocytosis, Haematologica, 10.3324/haematol.11233, 92, 7, 978-981, 2007.07, Perforin gene (PRF1) mutations cause the primary form of hemophagocytic lymphohistiocytosis (HLH). We report a genetic defect of PRF1 in a 62-year-old Japanese man with recurrent episodes of HLH. Sequencing of PRF1 from both peripheral blood mononuclear cells and nail clippings showed compound heterozygous mutation, including deletion of two base pairs at codons 1090 and 1091 (1090-1091delCT) and guanine-to-adenine conversion at nucleotide position 916 (916G→A). Although primary HLH has been detected in infants and children, genetic mutation of PRF1 or other genes should be considered a differential diagnosis of HLH even in the elderly.. |
| 69. |
Yoshikane Kikushige, Ken Takase, Keiko Sata, Ken Ichi Aoki, Akihiko Numata, Toshihiro Miyamoto, Takahiro Fukuda, Hisashi Gondo, Mine Harada, Koji Nagafuji, Repeated relapses of acute myelogenous leukemia in the isolated extramedullary sites following allogeneic bone marrow transplantations, Internal Medicine, 10.2169/internalmedicine.46.6384, 46, 13, 1011-1014, 2007.07, Isolated extramedullary (EM) relapses of acute myelogenous leukemia (AML) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) have been reported to be rare, and are usually followed by bone marrow relapses. We report a 49-year-old man with AML with the unfavorable chromosome abnormality 7q-, who was treated by allo-HSCT. Fifteen months after allo-HSCT, the patient initially developed a relapse only in his inguinal lymph nodes, and then bone marrow relapse became evident one month after the EM relapse. Subsequently, the patient received chemotherapy and a second allo-HSCT from another donor, but he suffered another relapse in different EM sites including the skin and central nervous system with a persistently normal marrow. This case is characterized by repeated relapses in isolated EM sites after allo-HSCT and suggests that the anti-leukemic effects of chemotherapy and/or graft-versus-leukemia effects in the EM sites might not be so uniformly effective as that in the marrow. Accordingly, we should be aware that AML relapses can occur repeatedly only in isolated EM sites post allo-HSCT, resulting in treatment failure and a poor prognosis.. |
| 70. |
K. Kamezaki, Y. Kikushige, A. Numata, T. Miyamoto, K. Takase, H. Henzan, K. Aoki, K. Kato, A. Nonami, T. Kamimura, F. Arima, K. Takenaka, N. Harada, T. Fukuda, S. Hayashi, Y. Ohno, T. Eto, M. Harada, K. Nagafuji, Rituximab does not compromise the mobilization and engraftment of autologous peripheral blood stem cells in diffuse-large B-cell lymphoma, Bone Marrow Transplantation, 10.1038/sj.bmt.1705649, 39, 9, 523-527, 2007.05, To investigate effects of the preautografting administration of rituximab on the mobilization and engraftment of peripheral blood stem cells (PBSC), we retrospectively analyzed the outcomes of 43 newly diagnosed diffuse-large B-cell lymphoma patients who received CHOP chemotherapy with or without rituximab as a first-line treatment before autologous PBSC transplantation (PBSCT). There was no difference in the number of CD34+ cells among PBSC between the non-rituximab and the rituximab groups. Although B-cells were completely depleted from PBSC in the rituximab group, we found no difference in the expression of CXCR-4, VLA-4 and c-Kit on PBSC, indicating that rituximab did not affect the expression of these adhesion molecules, which might be involved in the mechanism of mobilization. There was no significant difference in the recovery of neutrophils and platelets, transplant-related toxicity and post-transplant complications between the two groups. Despite the short follow-up, there was no significant difference in progression-free survival between the two groups. These results indicated no adverse effect of rituximab on the mobilization and engraftment of PBSC. Larger studies are required to determine the impact of rituximab on the mobilization and function of PBSC as well as whether a survival advantage exists in patients who undergo auto-PBSCT with rituximab.. |
| 71. |
Yoshikane Kikushige, Ken Takase, Toshihiro Miyamoto, Akihiko Numata, Kenjiro Kamezaki, Takahiro Fukuda, Koji Nagafuji, Hisashi Gondo, Mine Harada, Late relapse of acute myelogenous leukemia followed by epstein-barr virus-associated lymphoproliferative disease 11 years after allogeneic bone marrow transplantation, International Journal of Hematology, 84, 441-444, 2006.12. |
