Abstract
Targeted mutation assessment of 81 genes in 1021 adults with de novo acute myeloid leukemia (AML) identified recurrent mutations in the neurofibromin 1 (NF1) gene in 52 (5.1%) patients, including 36 (5.2%) younger and 16 (4.8%) older patients, which suggests NF1 belongs to the 20 most frequently mutated genes in adult AML. NF1 mutations were found throughout the gene, and comprised missense, frameshift, and nonsense mutations. One mutation hotspot, at amino acid threonine 676 (Thr676), was found in 27% of AML patients with NF1 mutations. NF1-mutated patients belonged more often to the adverse European LeukemiaNet (ELN) risk category than NF1 wild-type patients. Among patients aged <60 years, the presence of NF1 Thr676 mutations was associated with lower complete remission (CR) rates (P = 0.04) and shorter overall survival (OS; P = 0.01), as was the presence of any NF1 mutation in patients in the adverse ELN risk category (CR, P = 0.05; OS, P < 0.001). CR rates were also lower in NF1-mutated patients aged ≥60 years compared with NF1 wild-type patients (P = 0.001). In summary, our findings provide novel insights into the frequency of NF1 mutations in AML, and are suggestive of an adverse prognostic impact in patients treated with standard chemotherapy.
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Acknowledgements
The authors are grateful to the patients who consented to participate in these clinical trials and the families who supported them; to Donna Bucci and the CALGB/Alliance Leukemia Tissue Bank at The Ohio State University Comprehensive Cancer Center, Columbus, OH, for sample processing and storage services and Lisa J. Sterling and Christine Finks for data management. This work was supported in part by grants from the National Cancer Institute (Bethesda, Maryland, USA) [U10CA180821, U10CA180882 (to the Alliance), P30CA016058, P50CA140158, U10CA003927, U10CA032291, U10CA035279, U10CA047545, U10CA059518, U10CA101140, U10CA180850, U10CA180861, U10CA180866, U10CA180867, and U24CA196171]; the Leukemia Clinical Research Foundation; the Warren D. Brown Foundation; the Pelotonia Fellowship Program (to A-KE); and by an allocation of computing resources from The Ohio Supercomputer Center. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Author contributions
A-KE, KM, JCB, and CDB designed the study. A-KE, KM, AM, CJW, JSB, SEM, AdlC, JCB, and CDB contributed to the data interpretation. A-KE, KM, JK, and CDB wrote the manuscript. JK and DN performed statistical analysis. A-KE and SO performed laboratory-based research. KM, AJC, BLP, JEK, ESW, RMS, JCB, and CDB were involved directly or indirectly in the care of patients and/or sample procurement. All authors reviewed the manuscript and approved its final version.
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Eisfeld, AK., Kohlschmidt, J., Mrózek, K. et al. NF1 mutations are recurrent in adult acute myeloid leukemia and confer poor outcome. Leukemia 32, 2536–2545 (2018). https://doi.org/10.1038/s41375-018-0147-4
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DOI: https://doi.org/10.1038/s41375-018-0147-4
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