Aberrant Kupffer-like differentiation of hematopoietic stem cell is critical for the MDS pathogenesis in Setd2-deficient mice.

Histone methyltransferase SETD2 is recurrently mutated in hematopoietic malignancies. Our previous study showed that Setd2 deficiency impairs the self-renewal potential of murine hematopoietic stem cells (HSCs) and drives myelodysplastic syndrome (MDS)-like disorders. However, the precise oncogenic advantages conferred upon HSCs by Setd2 loss remain unclear. In this study, we found that Setd2 deficiency disrupted the fidelity of HSC lineage differentiation with preferential erythroid commitment and excessive macrophage priming, leading to ineffective erythropoiesis and the production of inflammatory embryonic-derived Kupffer cell (EmKC)-like cells. Notably, these EmKC-like cells exhibited HSC-independent self-renewal capability and remotely perturbed intramedullary hematopoiesis by inducing systemic inflammation. Furthermore, macrophage depletion effectively alleviated the inflammatory state and relieved MDS-like symptoms. Mechanistically, Setd2 loss leads to significant changes in DNA methylation and chromatin accessibility, resulting in the activation of Irf8. These findings suggest that the long-lived inflammatory cells may compensate for the HSC self-renewal defects, triggering systemic inflammation and driving hematopoietic malignant transformation. This paradigm provides a new understanding of hematopoietic malignancies with functional defects and exhaustion of HSCs.