Fusion-specific co-mutational architecture and treatment-response associations in pediatric core-binding factor acute myeloid leukemia: a multicenter exome-profiled cohort
7 affiliations
- 1Department of Pediatric Hematology, Fujian Institute of Hematology, Fujian Provincial Key Laboratory on Hematology, Fujian Medical University Union Hospital , ,
- 2Department of Pediatrics, Nanfang Hospital, Southern Medical University , ,
- 3Department of Pediatric Hematology/Oncology, Hematology and Oncology, Hunan Children’s Hospital , ,
- 4Department of Pediatric Hematology/Oncology, Shenzhen Children’s Hospital , ,
- 5Department of Pediatrics, Zhujiang Hospital of Southern Medical University , ,
- 6Department of Pediatrics, Paediatrics, People’s Hospital of Hunan Province , ,
- 7Paediatrics, The First Affiliated Hospital of Xiamen University , ,
Abstract
Introduction: Core-binding factor acute myeloid leukemia (CBF-AML) is defined by one of two founding fusions, but cooperating lesions may differ between fusion subtypes. We characterized the broader diagnostic co-mutational architecture of pediatric CBF-AML and examined its relationship with post-induction measurable residual disease (MRD) and outcome.
Methods: This retrospective analysis included 170 children with diagnostic whole-exome sequencing (WES) data (2019–2023), a subset of a reported 289-patient cohort. Candidate leukemia-associated variants were curated conservatively because matched normal samples were unavailable. Variant frequencies were compared between RUNX1::RUNX1T1 and CBFB::MYH11 AML with false-discovery-rate control. Associations with MRD were tested using Fisher’s exact test. Primary feature-specific Cox models for event-free survival (EFS) were adjusted only for fusion subtype and induction regimen; sensitivity analyses additionally addressed age and presenting WBC count, MRD, and transplantation.
Results: In a limited selection audit, fusion-subtype and FLT3-ITD distributions were similar between WES-included and non-included patients, whereas clinical-source KIT positivity was more frequent in the WES subset. The analytic cohort included 138 RUNX1::RUNX1T1 and 32 CBFB::MYH11 cases; 137 received FLAG-IDA, and 33 received DAE induction. At least one curated candidate variant was present in 135 patients (79.4%), and 69 (40.6%) had alterations in two or more genes. Tyrosine-kinase signaling alterations occurred in 115 patients (67.6%). RAS-pathway alterations were enriched in CBFB::MYH11 AML (53.1% vs. 19.6%; P < 0.001, q=0.002), driven principally by NRAS (50.0% vs. 15.2%; P < 0.001, q < 0.001). Chromatin-modifier alterations were numerically enriched in RUNX1::RUNX1T1 AML (24.6% vs. 6.2%; P = 0.028) but did not remain significant after multiplicity correction (q=0.114). After false-discovery-rate correction, no tested genomic feature was associated with MFC-MRD or molecular MRD positivity after the second induction. With a median follow-up of 33.2 months, 3-year EFS and overall survival were 84.2% and 89.8%, respectively. No baseline genomic feature showed a significant association with EFS in either the primary or expanded baseline-covariate models.
Conclusions: Among WES-profiled patients, pediatric CBF-AML showed fusion-specific co-mutational architecture, especially RAS-pathway enrichment in CBFB::MYH11 AML. In this WES-defined cohort, baseline genomic features were not established as response or outcome predictors. These findings are descriptive and hypothesis-generating; they do not support treatment-specific causal inference.
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BibTeX
@article{li2026fusionspecific,
title = {{Fusion-specific co-mutational architecture and treatment-response associations in pediatric core-binding factor acute myeloid leukemia: a multicenter exome-profiled cohort}},
author = {Mei Li and Chunxia Cai and Chunping Wu and Xiaoqin Feng and Mincui Zheng and Huirong Mai and Lihua Yang and Xiangling He and Hong Wen and Shaohua Le and Nainong Li and Yongzhi Zheng},
journal = {Frontiers in oncology},
year = {2026},
month = sep,
doi = {10.3389/fonc.2026.1897872},
url = {https://europepmc.org/article/PMC/PMC13661505},
note = {CC BY},
}
RIS
TY - JOUR
TI - Fusion-specific co-mutational architecture and treatment-response associations in pediatric core-binding factor acute myeloid leukemia: a multicenter exome-profiled cohort
AU - Mei Li
AU - Chunxia Cai
AU - Chunping Wu
AU - Xiaoqin Feng
AU - Mincui Zheng
AU - Huirong Mai
AU - Lihua Yang
AU - Xiangling He
AU - Hong Wen
AU - Shaohua Le
AU - Nainong Li
AU - Yongzhi Zheng
PY - 2026
DA - 2026/09/30
JO - Frontiers in oncology
DO - 10.3389/fonc.2026.1897872
UR - https://europepmc.org/article/PMC/PMC13661505
AB - Introduction: Core-binding factor acute myeloid leukemia (CBF-AML) is defined by one of two founding fusions, but cooperating lesions may differ between fusion subtypes. We characterized the broader diagnostic co-mutational architecture of pediatric CBF-AML and examined its relationship with post-induction measurable residual disease (MRD) and outcome. Methods: This retrospective analysis included 170 children with diagnostic whole-exome sequencing (WES) data (2019–2023), a subset of a reported 289-patient cohort. Candidate leukemia-associated variants were curated conservatively because matched normal samples were unavailable. Variant frequencies were compared between RUNX1::RUNX1T1 and CBFB::MYH11 AML with false-discovery-rate control. Associations with MRD were tested using Fisher’s exact test. Primary feature-specific Cox models for event-free survival (EFS) were adjusted only for fusion subtype and induction regimen; sensitivity analyses additionally addressed age and presenting WBC count, MRD, and transplantation. Results: In a limited selection audit, fusion-subtype and FLT3-ITD distributions were similar between WES-included and non-included patients, whereas clinical-source KIT positivity was more frequent in the WES subset. The analytic cohort included 138 RUNX1::RUNX1T1 and 32 CBFB::MYH11 cases; 137 received FLAG-IDA, and 33 received DAE induction. At least one curated candidate variant was present in 135 patients (79.4%), and 69 (40.6%) had alterations in two or more genes. Tyrosine-kinase signaling alterations occurred in 115 patients (67.6%). RAS-pathway alterations were enriched in CBFB::MYH11 AML (53.1% vs. 19.6%; P < 0.001, q=0.002), driven principally by NRAS (50.0% vs. 15.2%; P < 0.001, q < 0.001). Chromatin-modifier alterations were numerically enriched in RUNX1::RUNX1T1 AML (24.6% vs. 6.2%; P = 0.028) but did not remain significant after multiplicity correction (q=0.114). After false-discovery-rate correction, no tested genomic feature was associated with MFC-MRD or molecular MRD positivity after the second induction. With a median follow-up of 33.2 months, 3-year EFS and overall survival were 84.2% and 89.8%, respectively. No baseline genomic feature showed a significant association with EFS in either the primary or expanded baseline-covariate models. Conclusions: Among WES-profiled patients, pediatric CBF-AML showed fusion-specific co-mutational architecture, especially RAS-pathway enrichment in CBFB::MYH11 AML. In this WES-defined cohort, baseline genomic features were not established as response or outcome predictors. These findings are descriptive and hypothesis-generating; they do not support treatment-specific causal inference.
SN - 2234-943X
ER -