Personalized Single-Cell Proteogenomics to Distinguish Acute Myeloid Leukemia from Non-Malignant Clonal Hematopoiesis

Genetic mutations associated with acute myeloid leukemia (AML) can also be detected in age-related clonal hematopoiesis, making confident assignment of detected variants to malignancy challenging particularly in the post-treatment setting. This has implications for AML measurable residual disease monitoring, where the relationship between genetic sequencing and flow cytometry is also imperfect. We show here, using whole-genome-sequencing informed patient-personalized single-cell DNA and antibody-oligonucleotide sequencing, that it is possible to distinguish AML from clonal hematopoiesis and resolve the immunophenotypic identity of clonal architecture. Examples of AML arising both independently and from DNMT3A and TET2 mutated clones are shown. The ability to personalize single-cell proteogenomic assessment for individual patients based on leukemia-specific genomic features has implications for ongoing AML precision medicine efforts.