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.与急性髓系白血病（acute myeloid leukemia, AML）相关的遗传突变，亦可在年龄相关性克隆性造血中被检出，这使得将检出的变异精准归因于恶性肿瘤颇具挑战，尤其在治疗后场景中。该问题对AML的可测量残留病（measurable residual disease, MRD）监测具有重要意义，而此场景下基因测序与流式细胞术的关联同样并不完善。本研究通过全基因组测序（whole-genome sequencing）指导的患者个性化单细胞DNA测序与抗体寡核苷酸测序（antibody-oligonucleotide sequencing），证实可区分AML与克隆性造血，并解析克隆结构的免疫表型特征。本研究展示了两类AML案例：独立发生的AML，以及源自DNMT3A和TET2突变克隆的AML。基于白血病特异性基因组特征为个体患者定制单细胞蛋白质基因组学（single-cell proteogenomics）评估的能力，对当前AML精准医学研究具有重要价值。