2. Academic Validation
  3. Sequence-dependent splicing dysregulation drives therapy resistance in pediatric AML

Sequence-dependent splicing dysregulation drives therapy resistance in pediatric AML

  • Cell Rep Med. 2026 Jan 20;7(1):102542. doi: 10.1016/j.xcrm.2025.102542.
Yue Huang 1,  Peifang Xiao 2,  Lei Qin 3,  Li Gao 2,  Yang Zhao 4,  Jingru Sui 1,  Wenting Hu 5,  Lei Zhou 1,  Nan Han 1,  Xuan Lv 1,  Kunying Chen 1,  Yu Liu 6,  Hanhong Lin 1,  Shuhong Shen 5,  Omar Abdel-Wahab 7,  Shaoyan Hu 8,  Zhaoqi Liu 9,  Qianfei Wang 10
Affiliations

Affiliations

  • 1 Department of Computation Biology, China National Center for Bioinformation, Beijing 100101, China; Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China.
  • 2 Department of Hematology and Oncology, Children's Hospital of Soochow University, Suzhou 215025, China.
  • 3 Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China.
  • 4 Department of Computation Biology, China National Center for Bioinformation, Beijing 100101, China; Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China.
  • 5 Key Laboratory of Pediatric Hematology & Oncology of the Ministry of Health of China, Department of Hematology & Oncology, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai 200025, China.
  • 6 Pediatric Translational Medicine Institute, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai 200025, China.
  • 7 Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
  • 8 Department of Hematology and Oncology, Children's Hospital of Soochow University, Suzhou 215025, China. Electronic address: [email protected].
  • 9 Department of Computation Biology, China National Center for Bioinformation, Beijing 100101, China; Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China. Electronic address: [email protected].
  • 10 Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China. Electronic address: [email protected].
PMID: 41564858 DOI: 10.1016/j.xcrm.2025.102542
Abstract

Despite improvements in pediatric acute myeloid leukemia (AML) prognosis, about 30% of patients relapse after initial chemotherapy and have poor survival. However, the genetic basis of resistance remains unclear for most patients. To better understand the mechanistic basis and overcome treatment resistance, we analyze RNA Sequencing (RNA-seq) data from 702 pediatric AML patients. This effort uncovers a sequence-dependent splicing dysregulation in 36% of children linked to worse prognosis and a lower rate of complete remission. Surprisingly, this change in RNA splicing matches that induced by SRSF2 mutations, which are common in adult AML. Instead, we identify U2AF2 dysregulation as the driver of aberrant splicing in pediatric AML. The pathologic splicing changes are characterized by "weak" polypyrimidine tracts and are susceptible to modest U2AF2 reduction. These outcomes can be improved by pharmacologic modulation of PRMT Enzymes. Overall, these findings highlight the importance of modulating splicing defects to improve treatment response in pediatric AML.

Keywords

PRMT enzymes; U2AF2 downregulation; pediatric acute myeloid leukemia; splicing dysregulation; therapy resistance.

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