• Erica Reinig, Fei Yang, Elie Traer, Ranjana Arora, Shari Brown, Rogan Rattray, Rita Braziel, Guang Fan, Richard Press, and Jennifer Dunlap.
• From the Department of Pathology.
• Am. J. Clin. Pathol. 2016 Apr 1; 145 (4): 497-506.

ObjectivesOptimal integration of next-generation sequencing (NGS) into clinical practice in hematologic malignancies remains unclear. We evaluate the utility of NGS in myeloid malignancies.MethodsA 42-gene panel was used to sequence 109 cases of myelodysplastic syndrome (MDS, n = 38), chronic myelomonocytic leukemia (CMML, n = 14), myeloproliferative neoplasm (MPN, n = 24), and MDS and/or MPN transformed to acute myeloid leukemia (AML, n = 33).ResultsAt least one pathogenic mutation was identified in 74% of cases of MDS, 100% of CMMLs, and 96% of MPNs. In contrast, only 47% of cases of MDS (18/38) and 7% (1/14) of CMMLs exhibited abnormal cytogenetics. In diagnostically difficult cases of MDS or CMML with normal cytogenetics, NGS identified a pathogenic mutation and was critical in establishing the correct diagnosis. Spliceosomal genes and epigenetic modifiers were frequently mutated. Spliceosome mutations were also frequently detected in AML arising from MDS, CMML, or MPN (39%) compared with the reported rate in de novo AML (7%-14%).ConclusionsIn difficult cases of MDS or MPN, NGS facilitates diagnosis by detection of gene mutations to confirm clonality, and AMLs evolving from MDS or MPN carry frequent mutations in spliceosomal genes.© American Society for Clinical Pathology, 2016. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

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