Comparison of mutations in myelodysplasia and acute leukemia suggests divergent roles in initiation and progression.

mutation predicts adverse prognosis in many cancers, including myeloid neoplasms, but the mechanisms by which specific mutations affect disease biology, and whether they differ between disease categories, remain unknown. We analyzed mutations in 4 myeloid neoplasm subtypes (myelodysplastic syndrome [MDS], acute myeloid leukemia [AML], AML with myelodysplasia-related changes [AML-MRC], and therapy-related AML), and identified differences in mutation types, spectrum, and hot spots between disease categories and in comparison to solid tumors. Missense mutations in the DNA-binding domain were most common across all categories, whereas inactivating mutations and mutations outside the DNA binding domain were more common in AML-MRC than in MDS. mutations in MDS were more likely to retain transcriptional activity, and comutation profiles were distinct between disease categories and mutation types. Our findings suggest that mutated contributes to initiation and progression of neoplasia via distinct mechanisms, and support the utility of specific identification of mutations in myeloid malignancies.