Exploring treatment-driven subclonal evolution of prognostic triple biomarkers: Dual gene fusions and chimeric RNA variants in novel subtypes of acute myeloid leukemia patients with KMT2A rearrangement

作者：Yi Xu, Shengwen Calvin Li, Jeffrey Xiao, Qian Liu, Durga Cherukuri, Yan Liu, Saied Mirshahidi, Jane Xu, Xuelian Chen, Dadrastoussi Homa, Julian Olea, Kaijin Wu, Kevin R. Kelly, Fengzhu Sun, Ruihao Huang, Xiaoqi Wang, Qin Wen, Xi Zhang, Cristina Maria Ghiuzeli, Esther G Chong, Hisham Abdel‐Azim, Mark E. Reeves, David J. Baylink, Huynh Cao, Jiang F. Zhong · 发表于：Drug Resistance Updates · 年份：2025 · DOI：10.1016/j.drup.2024.101199 · 被引用次数：4 · 研究领域：Acute Myeloid Leukemia Research、Myeloproliferative Neoplasms: Diagnosis and Treatment、Cancer Genomics and Diagnostics

Chromosomal rearrangements (CR) initiate leukemogenesis in approximately 50% of acute myeloid leukemia (AML) patients; however, limited targeted therapies exist due to a lack of accurate molecular and genetic biomarkers of refractory mechanisms during treatment. Here, we investigated the pathological landscape of treatment resistance and relapse in 16 CR-AML patients by monitoring cytogenetic, RNAseq., and genome-wide changes among newly diagnosed, refractory, and relapsed AML. First, in FISH-diagnosed KMT2A (MLL gene, 11q23)/AFDN (AF6, 6q27)-rearrangement, RNA-sequencing identified an unknown CCDC32 (15q15.1)/CBX3 (7p15.2) gene fusion in both newly diagnosed and relapsed samples, which is previously unknown in KMT2A/AFDN-rearranged AML patients. Second, the unreported CCDC32/CBX3 gene fusion significantly affected the expression of wild-type genes of both CCDC32 (essential for embryonic development) and CBX3 (an oncogene for solid tumors) during the relapse, as demonstrated by Quantitative qPCR analyses. Third, we further confirmed the existence of triple biomarkers - KMT2A/AFDN (AF6, 6q27) rearrangement, the unknown CCDC32 (15q15.1)/CBX3 (7p15.2) gene fusion and chimeric RNA variants (treatment-resistant leukemic blasts harboring distinct breakpoints) in a 21-year-old male patient of rapid relapsed/refractory AML. Most intriguingly, in this work regarding 16 patients, patients 7 and 20 initially showed the KMT2A/AFDN gene fusion; upon relapse, patient 20 did not show this f...