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<p><i>NUP98</i> rearrangements represent a distinct, high-risk subtype of acute myeloid leukemia (AML), particularly in pediatric patients. However, their prevalence, genetic features, and clinical implications in adult AML remain poorly characterized. Using targeted-capture sequencing, we identified 41 cases with <i>NUP98</i> rearrangements among 1569 AML cases, representing the majority of 44 <i>NUP98</i>-rearranged cases detected across 4753 myeloid neoplasms. Fifteen distinct fusion partners were detected, with <i>NUP98::NSD1</i> and <i>NUP98::HOXA9</i> being the most frequent. Notably, two novel fusions—<i>NUP98::MEOX2</i> and <i>NUP98::HOXA6</i>—were identified. Co-mutations were relatively infrequent; <i>FLT3</i>-ITD and <i>WT1</i> mutations were the most common, while <i>NPM1</i> mutations were exclusive. <i>FLT3</i>-ITD was significantly enriched in <i>NUP98::NSD1</i> cases, whereas <i>TET2</i> mutations were more frequent in <i>NUP98::HOXA9</i> cases. Clonal hierarchy analysis suggested that <i>NUP98</i> rearrangements occur early in leukemogenesis. <i>NUP98</i>-rearranged AML exhibited higher relapse rates and shorter event-free survival. Specifically, <i>NUP98::NSD1</i> was associated with a poor induction response, whereas <i>NUP98::HOXA9</i> and <i>NUP98</i> fusions with other partners showed higher remission rates but frequent relapse. Allogeneic hematopoietic stem cell transplantation was associated with better survival, underscoring its significance. These findings reveal the genetic and clinical heterogeneity of <i>NUP98</i>-rearranged AML in adults and support its classification as a distinct entity, highlighting the need for fusion partner-specific therapeutic strategies.</p>

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NUP98 rearrangements in adult AML patients: evaluation of clinical implications and identification of novel fusion partners

  • 期刊论文

  • 发表日期：

    2026年1月7日

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  • Kazuhisa Chonabayashi,
  • Makoto Iwasaki,
  • Junya Kanda,
  • Hiroyuki Takamori,
  • Akinori Yoda,
  • Takahito Kawata,
  • Shumpei Mizuta,
  • Maki Sakurada,
  • Tadakazu Kondo,
  • Nobuhiro Hiramoto,
  • Yasunori Ueda,
  • Akihiko Gotoh,
  • Mitsumasa Watanabe,
  • Senji Kasahara,
  • Yuichi Ishikawa,
  • Hitoshi Kiyoi,
  • Kazunori Imada,
  • Kinuko Mitani,
  • Toshiyuki Kitano,
  • Nobuyoshi Arima,
  • Yukiharu Nakabo,
  • Nobuo Sezaki,
  • Nobuhiro Kanemura,
  • Takahiro Fukuda,
  • Motoshi Ichikawa,
  • Yasushi Miyazaki,
  • Shigeo Fuji,
  • Mamiko Sakata-Yanagimoto,
  • Yoshinori Yoshida,
  • Akifumi Takaori-Kondo,
  • Seishi Ogawa,
  • Yasuhito Nannya

摘要

NUP98 rearrangements represent a distinct, high-risk subtype of acute myeloid leukemia (AML), particularly in pediatric patients. However, their prevalence, genetic features, and clinical implications in adult AML remain poorly characterized. Using targeted-capture sequencing, we identified 41 cases with NUP98 rearrangements among 1569 AML cases, representing the majority of 44 NUP98-rearranged cases detected across 4753 myeloid neoplasms. Fifteen distinct fusion partners were detected, with NUP98::NSD1 and NUP98::HOXA9 being the most frequent. Notably, two novel fusions—NUP98::MEOX2 and NUP98::HOXA6—were identified. Co-mutations were relatively infrequent; FLT3-ITD and WT1 mutations were the most common, while NPM1 mutations were exclusive. FLT3-ITD was significantly enriched in NUP98::NSD1 cases, whereas TET2 mutations were more frequent in NUP98::HOXA9 cases. Clonal hierarchy analysis suggested that NUP98 rearrangements occur early in leukemogenesis. NUP98-rearranged AML exhibited higher relapse rates and shorter event-free survival. Specifically, NUP98::NSD1 was associated with a poor induction response, whereas NUP98::HOXA9 and NUP98 fusions with other partners showed higher remission rates but frequent relapse. Allogeneic hematopoietic stem cell transplantation was associated with better survival, underscoring its significance. These findings reveal the genetic and clinical heterogeneity of NUP98-rearranged AML in adults and support its classification as a distinct entity, highlighting the need for fusion partner-specific therapeutic strategies.