The Application of Targeted RNA Sequencing for KMT2A-Partial Tandem Duplication Identification and Integrated Analysis of Molecular Characterization in Acute Myeloid Leukemia.

Abstract

The partial tandem duplication of histone-lysine N-methyltransferase 2A (KMT2A-PTD) is an important genetic alteration in acute myeloid leukemia (AML) and is associated with poor clinical outcome. Accurate and rapid detection of KMT2A-PTD is important for outcome prediction and clinical management, but next-generation sequencing-based quantitative research is still lacking. In this study, we developed a targeted RNA-based next-generation sequencing panel, together with single primer enrichment and unique molecular identifiers, to identify KMT2A-PTD as well as AML-related gene fusions and other driver mutations. Our panel showed high sensitivity, accuracy, and reproducibility in detecting the fusion ratio of KMT2A-PTD. The mutation profile of KMT2A-PTD-positive patients with AML was characterized and different distribution patterns of driver mutations were found according to KMT2A-PTD fusion ratio level. Survival analyses revealed that the fusion ratio of KMT2A-PTD did not affect clinical outcome, but a novel molecular combination, namely, KMT2A-PTD/DNMT3A/FMS-like tyrosine kinase 3-internal tandem duplication, was associated with poor prognosis. Finally, it was shown that the dynamic changes in the KMT2A-PTD fusion ratio were consistent with the overall process of disease progression. In summary, we applied the unique molecular identifier-based RNA panel to quantitatively detect KMT2A-PTD and elucidate its clinical relevance, which complemented the integrative network of various genetic alterations in AML.

• Authors: Bing Dai, Hao Yu, Tingting Ma, Yichen Lei, Jiyue Wang, Yunxiang Zhang, Jing Lu, Han Yan, Lu Jiang, Bing Chen
• Journal: The Journal of molecular diagnostics : JMD (J Mol Diagn) Vol. 23 Issue 11 Pg. 1478-1490 (11 2021) ISSN: 1943-7811 [Electronic] United States
• PMID: 34384895 (Publication Type: Evaluation Study, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 Association for Molecular Pathology and American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Chemical References

• KMT2A protein, human
• Myeloid-Lymphoid Leukemia Protein
• Histone-Lysine N-Methyltransferase

Topics

• Adolescent
• Adult
• Aged
• Data Accuracy
• Female
• Gene Duplication
• Gene Fusion
• HL-60 Cells
• High-Throughput Nucleotide Sequencing (methods)
• Histone-Lysine N-Methyltransferase (genetics)
• Humans
• Leukemia, Myeloid, Acute (genetics, pathology)
• Male
• Middle Aged
• Molecular Diagnostic Techniques (methods)
• Myeloid-Lymphoid Leukemia Protein (genetics)
• Prognosis
• Reproducibility of Results
• Sensitivity and Specificity
• Sequence Analysis, RNA (methods)
• Tandem Repeat Sequences (genetics)
• Young Adult