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Integrated genetic and clinical prognostic factors for aggressive adult T-cell leukemia/lymphoma
Kameda T., Kataoka K., Kamiunten A., Hidaka M., Miyoshi H., Nakano N., Nosaka K., Yoshimitsu M., Yasunaga J.I., Kogure Y., Shide K., Miyahara M., Sakamoto T., Akizuki K., Hidaka T., Kubuki Y., Koya J., Kawano N., Yamashita K., Kawano H., Toyama T., Maeda K., Marutsuka K., Imaizumi Y., Kato K., Sugio T., Tokunaga M., Tashiro Y., Takaori-Kondo A., Miyazaki Y., Akashi K., Ishitsuka K., Matsuoka M., Ohshima K., Watanabe T., Kitanaka A., Utsunomiya A., Ogawa S., Shimoda K.
Haematologica 108 ( 8 ) 2178 - 2191 2023年8月
掲載種別：研究論文（学術雑誌） 出版者・発行元：Haematologica
The prognosis of aggressive adult T-cell leukemia/lymphoma (ATL) is poor, and allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative treatment. In order to identify favorable prognostic patients after intensive chemotherapy, and who therefore might not require upfront allo-HSCT, we aimed to improve risk stratification of aggressive ATL patients aged <70 years. The clinical risk factors and genetic mutations were incorporated into risk modeling for overall survival (OS). We generated the m7-ATLPI, a clinicogenetic risk model for OS, that included the ATL prognostic index (PI) (ATL-PI) risk category, and non-silent mutations in seven genes, namely TP53, IRF4, RHOA, PRKCB, CARD11, CCR7, and GATA3. In the training cohort of 99 patients, the m7-ATLPI identified a low-, intermediate-, and high-risk group with 2-year OS of 100%, 43%, and 19%, respectively (hazard ratio [HR] =5.46; P<0.0001). The m7-ATLPI achieved superior risk stratification compared to the current ATL-PI (C-index 0.92 vs. 0.85, respectively). In the validation cohort of 84 patients, the m7-ATLPI defined low-, intermediate-, and high-risk groups with a 2-year OS of 81%, 30%, and 0%, respectively (HR=2.33; P=0.0094), and the model again outperformed the ATL-PI (C-index 0.72 vs. 0.70, respectively). The simplified m7-ATLPI, which is easier to use in clinical practice, achieved superior risk stratification compared to the ATLPI, as did the original m7-ATLPI; the simplified version was calculated by summing the following: high-risk ATL-PI category (+10), low-risk ATL-PI category (−4), and non-silent mutations in TP53 (+4), IRF4 (+3), RHOA (+1), PRKCB (+1), CARD11 (+0.5), CCR7 (−2), and GATA3 (−3).
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Integrated genetic and clinical prognostic factors for aggressive adult T-cell leukemia/lymphoma
亀田 拓郎, 片岡 圭亮, 上運天 綾子, 日高 道弘, 三好 寛明, 中野 伸亮, 野坂 生郷, 吉満 誠, 安永 純一朗, 木暮 泰寛, 幣 光太郎, 宮原 正晴, 阪本 貴士, 秋月 渓一, 日髙 智徳, 久冨木 庸子, 古屋 淳史, 河野 徳明, 山下 清, 河野 浩, 外山 孝典, 前田 宏一, 丸塚 浩助, 今泉 芳孝, 加藤 光次, 杉尾 健志, 徳永 雅仁, 田代 幸恵, 髙折 晃史, 宮﨑 泰司, 赤司 浩一, 石塚 賢治, 松岡 雅雄, 大島 孝一, 渡邊 俊樹, 北中 明, 宇都宮 與, 小川 誠司, 下田 和哉
Haematologica 108 ( 8 ) 2178 - 2191 2023年8月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Ferrata Storti Foundation (Haematologica)
The prognosis of aggressive adult T-cell leukemia/lymphoma (ATL) is poor, and allogeneic hematopoietic stem-cell transplantation (allo-HSCT) is a curative treatment. To identify favorable prognostic patients after intensive chemotherapy, and who therefore might not require upfront allo-HSCT, we aimed to improve risk stratification of aggressive ATL patients aged <70 years. The clinical risk factors and genetic mutations were incorporated into risk modeling for overall survival (OS). We generated the m7-ATLPI, a clinicogenetic risk model for OS, that included the ATL prognostic index (PI) (ATL-PI) risk category, and non-silent mutations in seven genes, namely TP53, IRF4, RHOA, PRKCB, CARD11, CCR7, and GATA3. In the training cohort of 99 patients, the m7-ATLPI identified a low-, intermediate-, and high-risk group with 2-year OS of 100%, 43%, and 19%, respectively (hazard ratio [HR] 5.46, p < 0.0001). The m7-ATLPI achieved superior risk stratification compared to the current ATL-PI (C-index 0.92 vs. 0.85, respectively). In the validation cohort of 84 patients, the m7-ATLPI defined low-, intermediate-, and high-risk groups with a 2-year OS of 81%, 30%, and 0%, respectively (HR 2.33, p = 0.0094), and the model again outperformed the ATL-PI (C-index 0.72 vs. 0.70, respectively). The simplified m7-ATLPI, which is easier to use in clinical practice, achieved superior risk stratification compared to the ATL-PI, as did the original m7-ATLPI; the simplified version was calculated by summing the following: high-risk ATL-PI category (+10), low-risk ATL-PI category (−4), and non-silent mutations in TP53 (+4), IRF4 (+3), RHOA (+1), PRKCB (+1), CARD11 (+0.5), CCR7 (−2), and GATA3 (−3).
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Kameda T., Shide K., Kamiunten A., Kogure Y., Morishita D., Koya J., Tahira Y., Akizuki K., Yokomizo-Nakano T., Kubota S., Marutsuka K., Sekine M., Hidaka T., Kubuki Y., Kitai Y., Matsuda T., Yoda A., Ohshima T., Sugiyama M., Sashida G., Kataoka K., Ogawa S., Shimoda K.
Communications Biology 5 ( 1 ) 2022年12月
掲載種別：研究論文（学術雑誌） 出版者・発行元：Communications Biology
Adult T-cell leukemia/lymphoma (ATL) is caused by human T-cell leukemia virus type 1 (HTLV-1). In addition to HTLV-1 bZIP factor (HBZ), a leukemogenic antisense transcript of HTLV-1, abnormalities of genes involved in TCR-NF-κB signaling, such as CARD11, are detected in about 90% of patients. Utilizing mice expressing CD4+ T cell-specific CARD11(E626K) and/or CD4+ T cell-specific HBZ, namely CARD11(E626K)CD4-Cre mice, HBZ transgenic (Tg) mice, and CARD11(E626K)CD4-Cre;HBZ Tg double transgenic mice, we clarify these genes’ pathogenetic effects. CARD11(E626K)CD4-Cre and HBZ Tg mice exhibit lymphocytic invasion to many organs, including the lungs, and double transgenic mice develop lymphoproliferative disease and increase CD4+ T cells in vivo. CARD11(E626K) and HBZ cooperatively activate the non-canonical NF-κB pathway, IRF4 targets, BATF3/IRF4/HBZ transcriptional network, MYC targets, and E2F targets. Most KEGG and HALLMARK gene sets enriched in acute-type ATL are also enriched in double transgenic mice, indicating that these genes cooperatively contribute to ATL development.
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Prognosis of Indolent Adult T-Cell Leukemia/Lymphoma
Kameda T., Shide K., Tahira Y., Sekine M., Sato S., Ishizaki J., Takeuchi M., Akizuki K., Kamiunten A., Shimoda H., Toyama T., Maeda K., Yamashita K., Kawano N., Kawano H., Hidaka T., Yamaguchi H., Kubuki Y., Kitanaka A., Matsuoka H., Shimoda K.
Viruses 14 ( 4 ) 2022年4月
掲載種別：研究論文（学術雑誌） 出版者・発行元：Viruses
A retrospective chart survey of the clinical features of indolent adult T-cell leukemia/lymphoma (ATL) was conducted in the Miyazaki Prefecture, Japan. This study enrolled 24 smoldering-type ATLs, 10 favorable chronic-type ATLs, and 20 unfavorable chronic-type ATLs diagnosed between 2010 and 2018. Among them, 4, 3, and 10 progressed to acute-type ATLs during their clinical course. The median survival time (MST) in smoldering-type ATL and favorable chronic-type ATL was not reached, and their 4-year overall survival (OS) was 73% and 79%, respectively. Compared with this, the prognosis of unfavorable chronic-type ATL was poor. Its MST was 3.32 years, and the 4-year OS was 46% (p = 0.0095). In addition to the three features that determine the unfavorable characteristics of chronic-type ATL, namely, increased lactate dehydrogenase, increased blood urea nitrogen, and decreased albumin, the high-risk category by the indolent ATL-Prognostic Index, which was defined by an increment of soluble interleukin-2 receptor (sIL2-R) of >6000 U/mL, could explain the poor prognosis in indolent ATL patients. The level of sIL-2R might be an indicator of the initiation of therapy for indolent ATL.
DOI： 10.3390/v14040710
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Whole-genome landscape of adult T-cell leukemia/lymphoma
Kogure Y., Kameda T., Koya J., Yoshimitsu M., Nosaka K., Yasunaga J.i., Imaizumi Y., Watanabe M., Saito Y., Ito Y., McClure M.B., Tabata M., Shingaki S., Yoshifuji K., Chiba K., Okada A., Kakiuchi N., Nannya Y., Kamiunten A., Tahira Y., Akizuki K., Sekine M., Shide K., Hidaka T., Kubuki Y., Kitanaka A., Hidaka M., Nakano N., Utsunomiya A., Sica R.A., Acuna-Villaorduna A., Janakiram M., Shah U., Ramos J.C., Shibata T., Takeuchi K., Takaori-Kondo A., Miyazaki Y., Matsuoka M., Ishitsuka K., Shiraishi Y., Miyano S., Ogawa S., Ye B.H., Shimoda K., Kataoka K.
Blood 139 ( 7 ) 967 - 982 2022年2月
掲載種別：研究論文（学術雑誌） 出版者・発行元：Blood
Adult T-cell leukemia/lymphoma (ATL) is an aggressive neoplasm immunophenotypically resembling regulatory T cells, associated with human T-cell leukemia virus type-1. Here, we performed whole-genome sequencing (WGS) of 150 ATL cases to reveal the overarching landscape of genetic alterations in ATL. We discovered frequent (33%) loss-of-function alterations preferentially targeting the CIC long isoform, which were overlooked by previous exome-centric studies of various cancer types. Long but not short isoform–specific inactivation of Cic selectively increased CD4+CD25+Foxp3+ T cells in vivo. We also found recurrent (13%) 3′-truncations of REL, which induce transcriptional upregulation and generate gain-of-function proteins. More importantly, REL truncations are also common in diffuse large B-cell lymphoma, especially in germinal center B-cell–like subtype (12%). In the non-coding genome, we identified recurrent mutations in regulatory elements, particularly splice sites, of several driver genes. In addition, we characterized the different mutational processes operative in clustered hypermutation sites within and outside immunoglobulin/T-cell receptor genes and identified the mutational enrichment at the binding sites of host and viral transcription factors, suggesting their activities in ATL. By combining the analyses for coding and noncoding mutations, structural variations, and copy number alterations, we discovered 56 recurrently altered driver genes, including 11 novel ones. Finally, ATL cases were classified into 2 molecular groups with distinct clinical and genetic characteristics based on the driver alteration profile. Our findings not only help to improve diagnostic and therapeutic strategies in ATL, but also provide insights into T-cell biology and have implications for genome-wide cancer driver discovery.
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日常診療における再発/難治性ATLに対するTucidinostat療法の治療効果
上運天 綾子
第9回HTLV1学会学術集会 2023年11月12日
開催年月日： 2023年11月10日 - 2023年11月12日
記述言語：日本語 会議種別：口頭発表（一般）
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Loss of EZH2 does not affect the severity of murine myeloproliferative neoplasms with CALR mutation
上運天 綾子
第83回日本血液学会学術集会 2021年9月24日
開催年月日： 2021年9月23日 - 2021年9月25日
記述言語：日本語 会議種別：口頭発表（一般）
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Development of MALT1 inhibitor and its effect on ATL
上運天 綾子
第82回日本血液学会学術集会 2020年10月10日
開催年月日： 2020年10月10日 - 2020年11月8日
記述言語：日本語 会議種別：口頭発表（一般）
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宮崎県における骨髄異形成症候群に対するアザシチジン治療の有効性
上運天 綾子
第81回日本血液学会学術集会 2019年10月11日
開催年月日： 2019年10月11日 - 2019年10月13日
記述言語：日本語 会議種別：口頭発表（一般）
科研費（文科省・学振・厚労省）獲得実績 【 表示 ／ 非表示 】
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骨髄増殖性腫瘍におけるエピゲノム異常の役割
研究課題/領域番号：19K17834 2019年04月 - 2022年03月
科学研究費補助金 若手研究
担当区分：研究代表者