Mmrn1 expression defines a novel subset of hematopoietic stem cells and leukemia stem cells with great self-renewal potential.

Hematopoietic stem cells (HSC) are critical for lifelong blood cell generation. After mutation accumulation and functional disruption, HSC may transform into leukemic stem cells (LSC), leading to malignant hematological disorders. However, both HSC and LSC are highly heterogeneous, which hinders our comprehensive understanding of their biological characteristics and clinical application. Here, we identified multimerin 1 (Mmrn1) as a reliable marker for the most primitive HSC and LSC. We found that Mmrn1 was abundantly present in human and mouse HSC. Interestingly, HSC with high levels of Mmrn1 displayed increased quiescence and regenerative capacity, accompanied by megakaryocytic lineage commitment. Importantly, Mmrn1 deficiency gradually impairs HSC self-renewal under stress of transplantation due to reduced quiescence. Additionally, we noticed that Mmrn1 was specifically upregulated in acute myeloid leukemia (AML) cells, and its overexpression predicted poor patient prognosis. Further investigation revealed that Mmrn1 marked a subset of quiescent LSC responsible for AML initiation and development, and that deletion of Mmrn1 delays AML progression. Collectively, these data broaden our knowledge of stem cell heterogeneity in the context of normal and malignant hematopoiesis and advance the precision diagnosis and therapy of AML in the clinic.