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CLONAL HEMATOPOIESIS

Multi-omics on our multitudes

Nature Genetics volume 54, pages 1449–1450 (2022)Cite this article

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Clonal expansion of DNMT3A-mutant hematopoietic stem cells is a risk factor for myeloid malignancies and other morbidities. A new study uses multi-modal single-cell genomics to characterize the myeloid differentiation bias of DNMT3A-mutated clones, and finds preferential hypomethylation of binding motifs for key transcriptional regulators.

When Whitman wrote in Song of Myself, “I am large, I contain multitudes”, he was commenting on his own psychological complexities, but he could have just as well been referring to the diversity of hematopoietic stem cell (HSC) clones that he had. Over the past two decades, it has become increasingly clear that that the bone marrow niche contains numerous HSCs with somatically acquired mutations that can confer differential fitness advantages, some of which may preferentially expand to become dominant HSC clones in a process known as clonal hematopoiesis1. Clonal hematopoiesis predisposes to age-related hematological consequences such as an increased risk of progressing to blood cancers, including myelodysplastic syndromes and acute myeloid leukemia (AML), while also predisposing to age-related complications such as cardiovascular disease2. Somatic mutations that drive clonal hematopoiesis clones have been extensively characterized1, the most frequent of which involve the DNA methyltransferase DNMT3A. Mutations of DNMT3A at R882 have a dominant-negative effect on methylation activity and lead to a block in HSC differentiation and a resultant accumulation of HSCs in the bone marrow3,4. However, the ability to mechanistically study clonal hematopoiesis mutations in primary human samples has been limited by the admixture of mutated HSCs with non-mutated HSCs in vivo. In this issue of Nature Genetics, Nam et al.5 overcome this limitation by using single-cell genomic approaches to characterize the dysregulated hematopoietic differentiation that occurs in non-malignant clonal hematopoiesis driven by DNMT3A R882 mutations.

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Fig. 1: Single-cell multi-omic analyses show how DNMT3A R882 mutations bias hematopoietic fate decisions.

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Authors and Affiliations

  1. Division of Hematology/Oncology, Boston Children’s Hospital and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA

    Richard A. Voit & Vijay G. Sankaran

  2. Broad Institute of MIT and Harvard, Cambridge, MA, USA

    Richard A. Voit & Vijay G. Sankaran

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  1. Richard A. Voit
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  2. Vijay G. Sankaran
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Correspondence to Vijay G. Sankaran.

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Competing interests

V.G.S. serves as an advisor to and/or has equity in Branch Biosciences, Ensoma, Novartis, Forma and Cellarity, all unrelated to the present work. The authors have no other competing interests to declare.

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Voit, R.A., Sankaran, V.G. Multi-omics on our multitudes. Nat Genet 54, 1449–1450 (2022). https://doi.org/10.1038/s41588-022-01175-z

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