Clonal memory of cell division in humans diverges between healthy haematopoiesis and acute myeloid leukaemia

Clonal memory, a cellular property inherited across at least two divisions, is a key driver of cell heterogeneity. To uncover its roles in human haematopoiesis, we develop high-resolution ex vivo tools that track both division and fate commitment of individual primary human haematopoietic stem and progenitor cells (HSPCs). We show that human HSPCs display a clonal memory of division, as cells descending from the same ancestor cell divide synchronously over multiple generations. In parallel, HSPCs inherit a clonal memory of fate commitment, independently of lineage identity. Both forms of clonal memory persist over at least two divisions, across different HSPC commitment stages and cell culture conditions. In contrast, malignant haematopoiesis exhibits lower synchronicity, revealing a disruption of clonal memory in leukaemic cells. Epigenetic remodelling using a bromodomain inhibitor partially restores the clonal memory in division in leukaemic HSPCs, highlighting the plasticity of this trait and its potential for therapeutic modulation. Our findings position clonal memory as a key regulator of human haematopoietic stem cell behaviour. Demonstrating that clonal memory can be modulated opens avenues for tuning cell heterogeneity in healthy and pathological tissues. Healthy blood stem and progenitor cells display synchronised division across generations — a form of clonal memory lost in AML. A bromodomain inhibitor partially restores it, revealing a potential epigenetic vulnerability in leukaemia.