RNA sequencing as an alternative tool for detecting measurable residual disease in fusion gene-driven subtypes of AML

DNA sequencing-based measurable residual disease (MRD) detection has shown to be clinically relevant in AML. However, the same methodology cannot be applied to fusion gene-driven subtypes of AML such as core-binding factor AML (CBF-AML). A team led by researchers at the University of Toronto evaluated the effectiveness of using DNA and RNA sequencing in MRD detection and in tracking clonal dynamics in CBF-AML. Using RNA-seq, they were able to quantify expression levels of RUNX1-RUNX1T1 and CBFB-MYH11 at diagnosis and their levels of reduction during remission (P < 6.3e−05 and P < 2.2e−13). The level of reduction of RUNX1-RUNX1T1 as measured by RNA-seq and qPCR were highly correlated (R2 = 0.74, P < 5.4e−05). A decision tree analysis, based on 3-log reduction of RUNX1-RUNX1T1 and cKIT-D816mut at diagnosis, stratified RUNX1-RUNX1T1 AML patients into three subgroups. These three subgroups had 2-year overall survival rates at 87%, 74%, and 33% (P < 0.08) and 2-year relapse incidence rates at 13%, 42%, and 67% (P < 0.05). On the other hand, although low residual allelic burden was common, it was not associated with long-term outcome, indicating that mutation clearance alone cannot be interpreted as MRD-negative. Overall, this study demonstrates that the clinical utility of RNA sequencing as a potential tool for MRD monitoring in fusion gene-driven AML such as RUNX1-RUNX1T1 AML.

A prognostic model based on genetic features measured by RNA-sequencing


(a) A prognostic model using clinical and genetic information obtained from RNA-seq. Two variables were selected; 1. 3-log or deeper reduction of RUNX1-RUNX1T1 transcript level and 2. presence of cKIT-D816 mutation at diagnosis. Based these two factors, the algorithm identified three subgroups. (b) Overall survival and (c) cumulative incidence of relapse based on the defined risk groups.

Kim T, Moon JH, Ahn JS, Ahn SY, Jung SH, Yang DH, Lee JJ, Shin MG, Choi SH, Lee JY, Tyndel MS, Lee HY, Kim KH, Cai Y, Lee YJ, Sohn SK, Min YH, Cheong JW, Kim HJ, Zhang Z, Kim DDH. (2002) RNA sequencing as an alternative tool for detecting measurable residual disease in core-binding factor acute myeloid leukemia. Sci Rep 10(1):20119. [article]

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