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Acute myeloid leukemia

Clinical and molecular characterization of patients with acute myeloid leukemia and sole trisomies of chromosomes 4, 8, 11, 13 or 21

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Abstract

Sole trisomies of chromosomes 4, 8, 11, 13 and 21 account for 89–95% of all sole trisomies in adult AML patients. We analyzed clinical and molecular characteristics of 138 de novo AML patients with sole +4, +8, +11, +13 or +21, and compared them with AML patients with those trisomies occurring in addition to other chromosome abnormalities (non-sole trisomy) and with cytogenetically normal AML (CN-AML) patients. Mutations in methylation-related genes were most commonly observed within each sole trisomy group (+4, 55%; +8, 58%; +11, 71%; +13, 71%; +21, 75% of patients). Patients with sole trisomies, excluding +4, also had frequent mutations in spliceosome genes (+8, 43%; +11, 65%; +13, 65%; +21, 45% of patients). In contrast, +4 patients frequently had mutations in transcription factor genes (44%) and NPM1 (36%). While 48% of patients with sole trisomies harbored mutations in a spliceosome gene, spliceosome mutations were observed in only 24% of non-sole trisomy (n = 131, P < 0.001) and 19% of CN-AML patients (n = 716, P < 0.001). Our data suggest that mutations affecting methylation-related genes are a molecular hallmark of sole trisomies. Mutations in spliceosome genes were also commonly observed in many sole trisomy patients and represent a novel finding in this cytogenetic subgroup.

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Acknowledgements

The authors are grateful to the patients who consented to participate in the 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 for data management. This research was supported by the National Institutes of Health (NIH) grants R35 CA197734, 5P30 CA016058, U10 CA180861, CA101140, CA140158, CA196171, CA180821, CA180882, CA077658, UG1 CA233338, the Coleman Leukemia Research Foundation, the Pelotonia Fellowship Program (A-KE), and the D. Warren Brown Foundation.

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BB, A-KE, JK, KM, DN, CJW, JCB, and CDB contributed to the design and analysis of the study and the writing of the manuscript. A-KE, DP, and SO performed laboratory-based research. JSB performed the data processing. JK and DN performed statistical analysis. KM, JEK, BLP, AJC, RMS, JCB, and CDB were involved directly or indirectly in the care of patients and/or sample procurement. All authors read and agreed on the final version of the manuscript.

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Correspondence to Bhavana Bhatnagar.

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Bhatnagar, B., Eisfeld, AK., Kohlschmidt, J. et al. Clinical and molecular characterization of patients with acute myeloid leukemia and sole trisomies of chromosomes 4, 8, 11, 13 or 21. Leukemia 34, 358–368 (2020). https://doi.org/10.1038/s41375-019-0560-3

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