2025-12-08 マウントサイナイ医療システム (MSHS)
<関連情報>
- https://www.mountsinai.org/about/newsroom/2025/mount-sinai-study-finds-childhood-leukemia-aggressiveness-depends-on-timing-of-genetic-mutation
- https://aacrjournals.org/cancerdiscovery/article/doi/10.1158/2159-8290.CD-25-0556/770502/Ontogeny-Dictates-Oncogenic-Potential-Lineage
小児白血病における発癌能、細胞系統階層、治療反応は個体発生によって決定される Ontogeny Dictates Oncogenic Potential, Lineage Hierarchy, and Therapy Response in Pediatric Leukemia
Ke Wang;Shayan Saniei;Nikita Poddar;Isabella G. Martinez;Clifford Chao;Subrina Autar;Persephone Fiore;Saul Carcamo;Meghana Sreenath;Jack H. Peplinski;Rhonda E. Ries;Anna Huo-Chang Mei;Noshin Azra Rahman;Levan Mekerishvili;Miguel Quijada-Álamo;Grace Freed;Mimi Zhang;Katherine Lachman;Zayna Diaz;Manuel M. Gonzalez;Jing Zhang;Giang Pham;Dan Filipescu;Mirela Berisa;Tommaso Balestra;Noelle Wheeler;Julie A. Reisz;Angelo D’Alessandro;Daniel J. Puleston;Emily Bernstein;Jerry E. Chipuk;Mark Wunderlich;Sarah K. Tasian;Bridget K. Marcellino;Ian A. Glass;BDRL;Christopher M. Sturgeon;Dan A. Landau;Zhihong Chen;Eirini P. Papapetrou;Franco Izzo;Soheil Meshinchi;Dan Hasson;Elvin Wagenblast;BDRL
Cancer Discovery Published:December 06 2025
DOI:https://doi.org/10.1158/2159-8290.CD-25-0556
Abstract
Accumulating evidence links pediatric cancers to prenatal transformation events, yet the influence of the developmental stage on oncogenesis remains elusive. We investigated how hematopoietic stem cell developmental stages affect leukemic transformation, disease progression, and therapy response using a novel, humanized model of NUP98::NSD1-driven pediatric acute myeloid leukemia that is particularly aggressive with WT1 comutations. Fetal-derived hematopoietic stem cells readily transform into leukemia, and WT1 mutations further enhance stemness and alter lineage hierarchy. In contrast, stem cells from later developmental stages become progressively resistant to transformation. Single-cell analyses revealed that fetal-origin leukemia stem cells exhibit greater quiescence and reliance on oxidative phosphorylation than their postnatal counterparts. These differences drive distinct therapeutic responses despite identical oncogenic mutations. In patients, onco-fetal transcriptional programs correlate with worse outcomes. By targeting key vulnerabilities of fetal-origin leukemia cells, we identified combination therapies that significantly reduce aggressiveness, highlighting the critical role of ontogeny in pediatric cancer treatment.
Significance:
This study signifies the critical consequences of developmental timing in cancer initiation, revealing that identical driver mutations in fetal- versus postnatal-origin leukemias exhibit fundamentally distinct biology and treatment responses. Recognizing these developmental differences opens avenues for personalized therapeutic strategies, improving outcomes for pediatric patients with aggressive disease subtypes in leukemia.
