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<p>Minimally differentiated acute myeloid leukemia (AML-M0) is a rare and therapeutically challenging subgroup of AML characterized by immature hematopoietic stem cell-like features. To uncover the molecular basis, we conducted a comprehensive multi-omics analysis of 23 pediatric AML-M0 cases and compared them with 1483 leukemia samples. AML-M0 formed a characteristic group that exhibited global DNA hypermethylation and transcriptional suppression, particularly downregulation of genes related to oxidative phosphorylation and ribosome assembly compared to non-M0 AML. Genomic profiling revealed frequent loss-of-function alterations in <i>RUNX1</i> (26%) and <i>ETV6</i> (22%), along with activating mutations in signaling pathways (83%), such as <i>RAS</i>, <i>FLT3</i>, and <i>JAK</i>. Notably, <i>RUNX1</i> alterations were significantly associated with a poor prognosis. Functional analyses using a CRISPR/Cas9-mediated <i>RUNX1</i> knockout in a pediatric AML-M0 cell line showed stem cell-like transcriptional features and reduced expression of genes related to oxidative phosphorylation and ribosomal pathways. <i>RUNX1</i> disruption was also associated with reduced in vitro sensitivity to multiple drugs, including cytarabine and anthracyclines. Our study provides the most comprehensive molecular characterization of pediatric AML-M0 to date and identifies <i>RUNX1</i> alterations as important biological and clinical determinants. These insights highlight the potential strategies for precision therapy, including hypomethylating agents, signaling inhibitors, and metabolic targeting, to improve outcomes.</p>

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Multi-omics analysis of pediatric minimally differentiated acute myeloid leukemia reveals RUNX1-driven stemness and chemoresistance

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月29日

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  • Tatsuya Kamitori,
  • Satoshi Saida,
  • Kazuki Mitani,
  • Shinichi Tsujimoto,
  • Hiroaki Goto,
  • Hirofumi Shibata,
  • Ryo Akazawa,
  • Kiyotaka Isobe,
  • Hiroo Ueno,
  • Nobuyuki Kakiuchi,
  • Akiko M. Saito,
  • Mitsuteru Hiwatari,
  • Ko Kudo,
  • Shinsuke Hirabayashi,
  • Kohei Fukuoka,
  • Katsuyoshi Koh,
  • Takashi Taga,
  • Hirohito Kubota,
  • Itaru Kato,
  • Katsutsugu Umeda,
  • Souichi Adachi,
  • Tomoko Kawai,
  • Daisuke Tomizawa,
  • Junji Ikeda,
  • Norio Shiba,
  • Yasuhide Hayashi,
  • Seishi Ogawa,
  • Junko Takita

摘要

Minimally differentiated acute myeloid leukemia (AML-M0) is a rare and therapeutically challenging subgroup of AML characterized by immature hematopoietic stem cell-like features. To uncover the molecular basis, we conducted a comprehensive multi-omics analysis of 23 pediatric AML-M0 cases and compared them with 1483 leukemia samples. AML-M0 formed a characteristic group that exhibited global DNA hypermethylation and transcriptional suppression, particularly downregulation of genes related to oxidative phosphorylation and ribosome assembly compared to non-M0 AML. Genomic profiling revealed frequent loss-of-function alterations in RUNX1 (26%) and ETV6 (22%), along with activating mutations in signaling pathways (83%), such as RAS, FLT3, and JAK. Notably, RUNX1 alterations were significantly associated with a poor prognosis. Functional analyses using a CRISPR/Cas9-mediated RUNX1 knockout in a pediatric AML-M0 cell line showed stem cell-like transcriptional features and reduced expression of genes related to oxidative phosphorylation and ribosomal pathways. RUNX1 disruption was also associated with reduced in vitro sensitivity to multiple drugs, including cytarabine and anthracyclines. Our study provides the most comprehensive molecular characterization of pediatric AML-M0 to date and identifies RUNX1 alterations as important biological and clinical determinants. These insights highlight the potential strategies for precision therapy, including hypomethylating agents, signaling inhibitors, and metabolic targeting, to improve outcomes.