ABSTRACT
Somatic mutations in cancer genes have been ubiquitously detected in clonal expansions across healthy human tissue, including in clonal hematopoiesis. However, mutated and wildtype cells are morphologically and phenotypically similar, limiting the ability to link genotypes with cellular phenotypes. To overcome this limitation, we leveraged multi-modality single-cell sequencing, capturing the mutation with transcriptomes and methylomes in stem and progenitors from individuals with DNMT3A R882 mutated clonal hematopoiesis. DNMT3A mutations resulted in myeloid over lymphoid bias, and in expansion of immature myeloid progenitors primed toward megakaryocytic-erythroid fate. We observed dysregulated expression of lineage and leukemia stem cell markers. DNMT3A R882 led to preferential hypomethylation of polycomb repressive complex 2 targets and a specific sequence motif. Notably, the hypomethylation motif is enriched in binding motifs of key hematopoietic transcription factors, serving as a potential mechanistic link between DNMT3A R882 mutations and aberrant transcriptional phenotypes. Thus, single-cell multi-omics pave the road to defining the downstream consequences of mutations that drive human clonal mosaicism.
Competing Interest Statement
O.A.-W. has served as a consultant for H3B Biomedicine, Foundation Medicine Inc, Merck, Pfizer, and Janssen, and is on the Scientific Advisory Board of Envisagenics Inc and AIChemy; O.A.-W. has received prior research funding from H3B Biomedicine and LOXO Oncology unrelated to the current manuscript. I.G. serves on the advisory board of Bristol Myers Squibb, Takeda, Janssen, Sanofi and GlaxoSmithKline. D.A.L. has served as a consultant for Abbvie and Illumina, and is on the Scientific Advisory Board of Mission Bio and C2i Genomics; D.A.L. has received prior research funding from BMS and Illumina unrelated to the current manuscript.
Footnotes
↵‡ Jointly supervised this work;